Amondys 45
casimersen · DMD exon 45 (PMO)Conducted; negative (Ames, CHO chromosomal aberration, mouse micronucleus)
Wainua: genotox, carcinogenicity and repro: done or skipped?
eplontersen · TTR (ASO)
Genotoxicity
Conducted; negative (Ames, chromosomal aberration, mouse micronucleus)
“Eplontersen was negative in adequately conducted in vitro (Ames, chromosomal aberration) and in vivo (mouse bone marrow micronucleus) assays.”
Carcinogenicity
26-week Tg.rasH2 mouse study (PMR at FDA approval); no increase in neoplasms
“In a 26-week carcinogenicity study in male and female Tg.rasH2 mice, subcutaneous administration of eplontersen (0, 250, 500, or 1500 mg/kg) monthly for 26 weeks resulted in no increase in neoplasms.”
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
Combined fertility/EFD study in mouse (with surrogate); no adverse effects; no 2nd species, PPND or juvenile
“Potential effect of eplontersen on embryo-foetal development in a second species, pre- and post-natal development or juvenile toxicity were not investigated.”
Safety pharmacology
Single ascending-dose SC study in monkeys (CNS, CV, respiratory) plus in vitro hERG; no effects
“Safety pharmacology studies did not indicate any adverse effects on CNS, cardiovascular, or respiratory endpoints in male cynomolgus monkeys administered a single ascending dose of eplontersen of up to 24 mg/kg by SC injection.”
Genotox: Ames
Negative (bacterial reverse mutation)
“Eplontersen was negative in adequately conducted in vitro (Ames, chromosomal aberration) and in vivo (mouse bone marrow micronucleus) assays.”
Genotox: in vitro mammalian
Chromosomal aberration in Chinese hamster lung cells: negative
“Eplontersen was negative for genotoxicity in in vitro (bacterial reverse mutation, chromosomal aberration in Chinese hamster lung cells) and in vivo (mouse bone marrow micronucleus) assays.”
Genotox: in vivo
Mouse bone marrow micronucleus: negative (up to 2000 mg/kg SC)
“In vivo, two s.c. injections of up to 2000 mg/kg eplontersen did not induce micronuclei in the bone marrow of mice.”
Carcinogenicity model
26-week Tg.rasH2 mouse, SC up to 1500 mg/kg/month; not tumorigenic
“Eplontersen was not tumorigenic following s.c. injections up to 1500 mg/kg/month in a GLP-compliant 26 weeks carcinogenicity study in transgenic Tg.rasH2 mice.”
Carcinogenicity timing
26-week Tg.rasH2 mouse not assessed at the marketing application; postmarketing requirement
“The carcinogenic potential of eplontersen has not been assessed. A 26-week carcinogenicity study in the tg.ratH2 mouse will be a post-marketing requirement.”
hERG / QT
No hERG inhibition up to 300 µM
“Eplontersen concentrations up to 300 µM did not inhibit hERG-currents in vitro.”
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)
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