Amondys 45
casimersen · DMD exon 45 (PMO)Conducted; negative (Ames, CHO chromosomal aberration, mouse micronucleus)
Zanvastro: genotox, carcinogenicity and repro: done or skipped?
zilganersen · GFAP (ASO)
Genotoxicity
Conducted: Ames, in vitro chromosomal aberration, mouse micronucleus; all negative
“Zilganersen was negative in the Ames, in vitro chromosomal aberration, and mouse bone marrow micronucleus assays.”
Carcinogenicity
Not conducted pre-approval; Tg.rasH2 mouse and 2-year rat studies required as PMRs
“No new studies were provided. The Division agreed these studies can be completed as post-marketing requirements (PMRs) given the benefit:risk and unmet medical need.”
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
Combined fertility/EFD in mouse (SC), no adverse effects; rabbit EFD and PPND deferred to PMRs
“No adverse fertility or embryofetal developmental effects were observed in mouse administered zilganersen subcutaneously at doses of 0, 10, 30, or 60 mg/kg once every 2 weeks.”
Safety pharmacology
Incorporated into 9-month monkey study (no findings); in vitro hERG minimal; auditory startle in juvenile mice
“No zilganersen-related safety pharmacology findings were identified in the 9-month monkey study”
Genotox: Ames
Negative
“Zilganersen was negative in the Ames, in vitro chromosomal aberration, and mouse bone marrow micronucleus assays.”
Genotox: in vitro mammalian
In vitro chromosomal aberration: negative
“Zilganersen was negative in the Ames, in vitro chromosomal aberration, and mouse bone marrow micronucleus assays.”
Genotox: in vivo
Mouse bone marrow micronucleus: negative
“Zilganersen was negative in the Ames, in vitro chromosomal aberration, and mouse bone marrow micronucleus assays.”
Carcinogenicity model
Not conducted
“Long-term studies to assess the carcinogenic potential of zilganersen have not been conducted.”
Carcinogenicity timing
6-month Tg.rasH2 mouse and 2-year rat: postmarketing requirements
“5053-1: Conduct a 6-month carcinogenicity study of zilganersen in Tg.rasH2 mice to assess tumorigenic potential. 5053-2: Conduct a 2-year carcinogenicity study of zilganersen in rats to assess tumorigenic potential.”
hERG / QT
Minimal hERG inhibition (IC50 >150 µM); no safety pharmacology findings in 9-month monkey study
“No zilganersen-related safety pharmacology findings were identified in the 9-month monkey study, and hERG inhibition in HEK-293 (human embryonic kidney-293) cells was minimal (IC50>150µM).”
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)
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