Amondys 45
casimersen · DMD exon 45 (PMO)Conducted; negative (Ames, CHO chromosomal aberration, mouse micronucleus)
Tegsedi: genotox, carcinogenicity and repro: done or skipped?
inotersen · TTR (ASO)
Genotoxicity
Conducted; negative (Ames, CHL chromosomal aberration, mouse micronucleus)
“Inotersen was negative in an adequate standard battery of in vitro (Ames, chromosomal aberration in Chinese hamster lung cells) and in vivo (CD-1 mouse micronucleus at single doses up to 2000 mg/kg SC) assays.”
Carcinogenicity
26-week rasH2 mouse (inotersen + surrogate) negative; 2-year rat study as postmarketing requirement
“In transgenic (TgRasH2) mice, subcutaneous administration of inotersen (0, 10, 30, or 80 mg/kg) or a species-specific surrogate (ISIS 401724; 30 mg/kg) weekly for 26 weeks resulted in no drug-related increase in tumors.”
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
Full battery in mouse (FEED/EFD, PPND, with surrogate) and rabbit EFD; only reduced fetal weight at rabbit high dose
“A full battery of reproductive and development studies was conducted in CD-1 mouse and New Zealand White rabbit.”
Safety pharmacology
Standalone core battery: mouse CNS, telemetered monkey CV/respiratory, hERG; no adverse effects
“No adverse effects of inotersen were observed on a core battery of safety pharmacology parameters in CNS in CD-1 mouse (CNS) or cynomolgus monkey (cardiovascular and respiratory) following acute SC doses of up to 300 or 40 mg/kg, respectively.”
Genotox: Ames
Negative (Ames)
“Inotersen was negative in an adequate standard battery of in vitro (Ames, chromosomal aberration in Chinese hamster lung cells) and in vivo (CD-1 mouse micronucleus at single doses up to 2000 mg/kg SC) assays.”
Genotox: in vitro mammalian
Chromosomal aberration in Chinese hamster lung cells: negative
“Inotersen was negative in an adequate standard battery of in vitro (Ames, chromosomal aberration in Chinese hamster lung cells) and in vivo (CD-1 mouse micronucleus at single doses up to 2000 mg/kg SC) assays.”
Genotox: in vivo
CD-1 mouse micronucleus (single SC doses up to 2000 mg/kg): negative
“Inotersen was negative in an adequate standard battery of in vitro (Ames, chromosomal aberration in Chinese hamster lung cells) and in vivo (CD-1 mouse micronucleus at single doses up to 2000 mg/kg SC) assays.”
Carcinogenicity model
26-week TgRasH2 mouse with inotersen and mouse surrogate ISIS 401724: no drug-related tumors
“In transgenic (TgRasH2) mice, subcutaneous administration of inotersen (0, 10, 30, or 80 mg/kg) or a species-specific surrogate (ISIS 401724; 30 mg/kg) weekly for 26 weeks resulted in no drug-related increase in tumors.”
Carcinogenicity timing
rasH2 mouse study completed; 2-year rat study ongoing at approval, results submitted post approval
“No carcinogenic potential was identified in a short-term carcinogenicity study in transgenic rasH2 mice. A 2 year carcinogenicity study in rats is currently ongoing and results will be submitted post approval.”
hERG / QT
No hERG inhibition up to 300 µM; no CV/respiratory effects in telemetered monkeys up to 40 mg/kg SC
“In safety pharmacology studies, inotersen did not inhibit hERG currents in vitro up to 300 µM and did not affect cardiovascular or respiratory function of telemetered monkeys following s.c. injections up to 40 mg/kg.”
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)
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