Amondys 45
casimersen · DMD exon 45 (PMO)Conducted; negative (Ames, CHO chromosomal aberration, mouse micronucleus)
Qalsody: genotox, carcinogenicity and repro: done or skipped?
tofersen · SOD1 (ASO)
Genotoxicity
Conducted; negative (Ames, CHL chromosomal aberration, mouse micronucleus)
“Tofersen was negative in a complete battery of genetic toxicology studies.”
Carcinogenicity
Not conducted pre-approval (severity of indication); to be assessed post-approval
“Due to the severity of the indication, the carcinogenic potential of tofersen is to be conducted post-approval.”
Reproductive & developmental
Mouse fertility (seminiferous tubule degeneration, NOAEL 10 mg/kg), mouse/rabbit EFD and mouse PPND negative; pharmacologically non-relevant species
“There were no effects on embryofetal development in CD1 mouse or NZW rabbit, or on pre- and postnatal development in CD1 mouse.”
Safety pharmacology
Incorporated into single-dose IT rat (CNS) and 13-week IT monkey study (CNS, CV, respiratory); hERG in vitro
“Safety pharmacology assessments following IT administration of tofersen were incorporated into a single dose study in male and female SD rats (CNS) and a 13-week repeat (Q2W) dose toxicity study in cynomolgus monkeys (CNS, CV, and respiratory).”
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
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)
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