Amondys 45
casimersen · DMD exon 45 (PMO)Conducted; negative (Ames, CHO chromosomal aberration, mouse micronucleus)
Rivfloza: genotox, carcinogenicity and repro: done or skipped?
nedosiran · LDHA (siRNA)
Genotoxicity
Conducted; negative (Ames, in vitro micronucleus, in vivo mouse micronucleus)
“Nedosiran was negative in the bacterial reverse mutation assay and did not induce micronuclei in mammalian cells in vitro or in vivo (Table 48).”
Carcinogenicity
Not conducted pre-approval; deferred to postmarketing (TgRasH2 and 2-year studies)
“The carcinogenic potential of nedosiran has not been assessed. The Agency agrees that carcinogenicity studies can be conducted postmarketing.”
Reproductive & developmental
Mouse FEED/EFD/PPND clean; rabbit EFD: fetal loss and malformations at >=0.7-2x MRHD (unexplained, off-target)
“Higher postimplantation loss and lower numbers of live fetuses were observed at doses of ≥6 mg/kg/dose (0.7x the MRHD, based on body surface area), and fetal cardiovascular and skeletal malformations were observed at a dose of 20 mg/kg/dose (2x the MRHD).”
Safety pharmacology
Stand-alone in vitro hERG plus CNS/respiratory/CV studies in conscious monkeys; no significant effects
“Nedosiran had no significant adverse effect on central nervous system, respiratory, or cardiovascular function of cynomolgus monkeys at doses up to 300 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
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
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
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)
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