Amondys 45
casimersen · DMD exon 45 (PMO)Conducted; negative (Ames, CHO chromosomal aberration, mouse micronucleus)
Redemplo: genotox, carcinogenicity and repro: done or skipped?
plozasiran · APOC3 (siRNA)
Genotoxicity
Conducted: Ames, in vitro chromosomal aberration (TK6), in vivo mouse micronucleus; not genotoxic
“Plozasiran was not genotoxic when tested in the in vitro bacterial mutation (Ames) assay, in vitro chromosomal aberration assay in cultured TK6 lymphoblastoid cells, and in vivo micronucleus assay in mice.”
Carcinogenicity
Conducted: 26-week Tg.rasH2 mouse negative; 2-year rat study ongoing
“In the 26-week study in Tg.rasH2 mice, administration of plozasiran by the SC route Q8W up to 120 mg/kg (~50-fold clinical dose, based on AUC) did not increase the incidence of tumors in male or female mice.”
Reproductive & developmental
Conducted in rat: fertility (NOAEL 50 mg/kg), EFD (NOAEL 60 mg/kg), PPND (pup survival reduced at 24 mg/kg and above); no rabbit
“The NOAEL for male and female fertility was 50 mg/kg (19-fold the human dose, based on BSA).”
Safety pharmacology
Standalone monkey CV study (single SC dose up to 300 mg/kg); hERG not warranted
“Plozasiran had no adverse effect on cardiovascular function in conscious cynomolgus monkeys following a single dose of SC injection 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
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)
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