Amondys 45
casimersen · DMD exon 45 (PMO)Conducted; negative (Ames, CHO chromosomal aberration, mouse micronucleus)
Vitravene: genotox, carcinogenicity and repro: done or skipped?
fomivirsen · CMV IE2 mRNA (ASO)
Genotoxicity
Conducted: mutagenic potential evaluated in in vitro and in vivo assays
“The mutagenic potentials of fomivirsen were evaluated in both in vitro and in vivo systems and results were summarized in the following table.”
Carcinogenicity
Not conducted; waiver requested citing lack of meaningful systemic exposure
“A waiver from performing carcinogenicity studies was requested by the sponsor. The sponsor stated that "lack of meaningful systemic exposure, additional systemic toxicity studies are neither relevant nor useful for assessing the safety profile of this compound".”
Reproductive & developmental
Not conducted; no reproductive toxicology information provided
“No information was provided.”
Safety pharmacology
ECG in repeat-dose intravitreal monkey study: no PR, QRS or QT changes, arrhythmia or conduction disturbances
“Neither significant changes in P-R, QRS, and Q-T intervals nor arrhythmia nor conduction disturbances were observed.”
Genotox: Ames
Not mutagenic (Salmonella)
“Ames Salmonella syphimurium: T498, TAI00, 6.7 - 5000 up/plate Not mutagenic”
Genotox: in vitro mammalian
Chromosome aberration in CHO-K1 cells: not clastogenic; mouse lymphoma assay result not legible
“Chromosome CHO-KI cells Aberration TReport N° ISIS 2922-1S01 : DETO 10, 800) , 800, or Not clastogenic”
Genotox: in vivo
Mouse bone marrow micronucleus assay conducted; result not stated legibly
“Micronucleus ICR mice -Bone Marrow Cells”
Carcinogenicity model
Not conducted: waiver citing lack of meaningful systemic exposure
“A waiver from performing carcinogenicity studies was requested by the sponsor. The sponsor stated that "lack of meaningful systemic exposure, additional systemic toxicity studies are neither relevant nor useful for assessing the safety profile of this compound".”
Carcinogenicity timing
Not required: FDA accepted the carcinogenicity waiver
“the review division would accept the request from the sponsor for a waiver of carcinogenicity studies on fomivirsen.”
hERG / QT
No hERG assay; no PR, QRS or QT changes, arrhythmia or conduction disturbances on ECG in repeat-dose monkey study
“Neither significant changes in P-R, QRS, and Q-T intervals nor arrhythmia nor conduction disturbances were observed.”
Same question, other oligonucleotides
Amvuttra
vutrisiran · TTR (siRNA)Conducted: Ames, human lymphocyte chromosome aberration, rat micronucleus; all negative
Cyfendus
anthrax vaccine adsorbed, adjuvanted · TLR9 (CpG 7909 adjuvant)Not conducted
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
Heplisav-B
hepatitis B vaccine (recombinant), adjuvanted · TLR9 (CpG 1018 adjuvant)CpG adjuvant negative in Ames, in vitro chromosome aberration and in vivo mouse micronucleus tests
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)
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