Amondys 45
casimersen · DMD exon 45 (PMO)Conducted; negative (Ames, CHO chromosomal aberration, mouse micronucleus)
Rytelo: genotox, carcinogenicity and repro: done or skipped?
imetelstat · Telomerase (oligo)
Genotoxicity
Conducted; negative (Ames, in vitro micronucleus, in vivo mouse micronucleus)
“In genetic toxicity studies, imetelstat was not mutagenic in the in vitro bacterial reverse mutation assay.”
Carcinogenicity
Not conducted pre-approval; mouse and rat carcinogenicity studies required as PMRs
“To address the carcinogenicity risk assessment of imetelstat, there will be separate Post Marketing Requirements (PMRs) for carcinogenicity assessments in the mouse and rat species.”
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
EFD in mice and rabbits: post-implantation loss/resorptions; no fertility or PPND studies
“Increased rates of post-implantation loss and early resorptions that resulted in a decreased number of viable fetuses and litter size per animal, and decreased uterine weight were observed at”
Safety pharmacology
Stand-alone telemetered monkey CV/CNS/respiratory study plus ECG in 9-month monkey study; no effects
“There were no test article-related changes observed in the cardiovascular, central nervous or respiratory systems.”
Genotox: Ames
Negative (bacterial reverse mutation)
“In genetic toxicity studies, imetelstat was not mutagenic in the in vitro bacterial reverse mutation assay.”
Genotox: in vitro mammalian
In vitro micronucleus in human lymphocytes: negative
“The drug was also negative for clastogenicity in both the in vitro micronucleus assay in human lymphocyte cultures and the in vivo mouse bone marrow micronucleus assay.”
Genotox: in vivo
Mouse bone marrow micronucleus: negative
“The drug was also negative for clastogenicity in both the in vitro micronucleus assay in human lymphocyte cultures and the in vivo mouse bone marrow micronucleus assay.”
Carcinogenicity model
Not conducted pre-approval; mouse and rat studies to follow as PMRs
“To address the carcinogenicity risk assessment of imetelstat, there will be separate Post Marketing Requirements (PMRs) for carcinogenicity assessments in the mouse and rat species.”
Carcinogenicity timing
Not conducted before approval; mouse and rat carcinogenicity studies are postmarketing requirements
“To address the carcinogenicity risk assessment of imetelstat, there will be separate Post Marketing Requirements (PMRs) for carcinogenicity assessments in the mouse and rat species.”
hERG / QT
No hERG inhibition up to 750 µg/mL (~150 µM)
“Imetelstat did not inhibit hERG currents up to a concentration of 750 µg/ml (~150 µM).”
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)
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