Amondys 45
casimersen · DMD exon 45 (PMO)Conducted; negative (Ames, CHO chromosomal aberration, mouse micronucleus)
Dawnzera: genotox, carcinogenicity and repro: done or skipped?
donidalorsen · Prekallikrein / KLKB1 (ASO)
Genotoxicity
Conducted: in vitro Ames, CHL chromosomal aberration and in vivo mouse bone marrow micronucleus; no genotoxicity
“Donidalorsen was evaluated for genotoxicity potential both in vitro and in vivo.”
Carcinogenicity
Conducted: 27-week Tg.rasH2 mouse study; 2-year rat study ongoing at time of review
“its tumorigenic potential has been evaluated in a 27-week carcinogenicity study in Tg.rasH2 mice, and a 2-yr carcinogenicity study in Sprague Dawley (SD) rats, which is ongoing”
Reproductive & developmental
Conducted in mice only: combined fertility/EFD and PPND studies (with surrogate group); NOAEL top dose; no rabbit EFD
“Reproductive and developmental toxicity studies were conducted in one species only, namely CD-1 mice”
Safety pharmacology
Standalone monkey CV/respiratory/neurobehavioural study (up to 30 mg/kg) and hERG; no adverse effects
“An in vivo safety pharmacology study conducted in the monkey indicated that donidalorsen had no adverse effects on cardiovascular, respiratory or neurobehavioural parameters at a dose of up to 30 mg/kg.”
Genotox: Ames
Negative (bacterial reverse mutation)
“Donidalorsen was negative for genotoxicity (mutagenicity or clastogenicity) in the in vitro bacterial reverse mutation test (Ames assay), in vitro chromosome aberration assay in cultured Chinese Hamster Lung (CHL) cells, and bone marrow micronucleus assay in mice.”
Genotox: in vitro mammalian
Chromosome aberration in Chinese hamster lung cells: negative
“Donidalorsen was negative for genotoxicity (mutagenicity or clastogenicity) in the in vitro bacterial reverse mutation test (Ames assay), in vitro chromosome aberration assay in cultured Chinese Hamster Lung (CHL) cells, and bone marrow micronucleus assay in mice.”
Genotox: in vivo
Mouse bone marrow micronucleus: negative (up to 2000 mg/kg SC)
“In the in vivo mouse bone marrow micronucleus assay, two SC administrations of donidalorsen at doses up to 2000 mg/kg did not induce an increase in micronucleated polychromatic erythrocytes (MNPCE).”
Carcinogenicity model
27-week Tg.rasH2 mouse (completed); 2-year SD rat (ongoing)
“The carcinogenicity assessment for donidalorsen includes a completed 27-week study in Tg.rasH2 mice and a 2-year study in SD rats that is ongoing with the final report due in Q4 2025.”
Carcinogenicity timing
27-week Tg.rasH2 mouse completed; 2-year SD rat ongoing at approval, final report due Q4 2025
“The carcinogenicity assessment for donidalorsen includes a completed 27-week study in Tg.rasH2 mice and a 2-year study in SD rats that is ongoing with the final report due in Q4 2025.”
hERG / QT
No significant hERG inhibition; estimated IC50 >300 µM
“Donidalorsen did not statistically inhibit hERG current in HEK-293 cells stably transfected with hERG cDNA with an estimated IC50 greater than 300μM”
Same question, other oligonucleotides
Amvuttra
vutrisiran · TTR (siRNA)Conducted: Ames, human lymphocyte chromosome aberration, rat micronucleus; all negative
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)
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