Amondys 45
casimersen · DMD exon 45 (PMO)Conducted; negative (Ames, CHO chromosomal aberration, mouse micronucleus)
Qfitlia: genotox, carcinogenicity and repro: done or skipped?
fitusiran · Antithrombin / SERPINC1 (siRNA)
Genotoxicity
Conducted: bacterial reverse mutation, in vitro chromosomal aberration (human lymphocytes), rat bone-marrow micronucleus; all negative
“Fitusiran was not mutagenic or clastogenic in a battery of genetic toxicity studies”
Carcinogenicity
Conducted: 2-year rat and 26-week Tg-rasH2 mouse studies; not carcinogenic
“In a 2-year carcinogenicity study in Sprague Dawley rats, fitusiran was not carcinogenic up to the highest dose tested”
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
Male fertility/early embryonic development in 26-week rat study (no effects); no female reproductive or EFD studies (hemophilia almost exclusively male)
“Fitusiran was not tested in reproduction studies in female animals because hemophilia A and B occur almost exclusively in males.”
Safety pharmacology
Dedicated: hERG assay and GLP telemetry monkey CV/respiratory study (up to 10 mg/kg SC); no effects
“In a GLP safety pharmacology study that evaluated both cardiovascular and respiratory function, male telemetered cynomolgus monkeys were subcutaneously administered a single dose of vehicle”
Genotox: Ames
Negative (bacterial reverse mutation)
“Fitusiran was not mutagenic or clastogenic in a battery of genetic toxicity studies (i.e., in vitro bacterial reverse mutation assay, in vitro chromosomal aberration assay in human peripheral blood lymphocytes; in vivo bone marrow micronucleus test in rats).”
Genotox: in vitro mammalian
Chromosomal aberration in human peripheral blood lymphocytes: negative
“Fitusiran was not mutagenic or clastogenic in a battery of genetic toxicity studies (i.e., in vitro bacterial reverse mutation assay, in vitro chromosomal aberration assay in human peripheral blood lymphocytes; in vivo bone marrow micronucleus test in rats).”
Genotox: in vivo
Rat bone marrow micronucleus: negative
“Fitusiran was not mutagenic or clastogenic in a battery of genetic toxicity studies (i.e., in vitro bacterial reverse mutation assay, in vitro chromosomal aberration assay in human peripheral blood lymphocytes; in vivo bone marrow micronucleus test in rats).”
Carcinogenicity model
2-year rat and 26-week TgRasH2 mouse
“The Sponsor submitted final reports for carcinogenicity studies of fitusiran 1. A 26-week study in TgRasH2 mouse study-at3-glp17-001.pdf, 2. A 2-year study in rats study-car0186.pdf.”
Carcinogenicity timing
26-week TgRasH2 mouse and 2-year rat studies completed; final reports submitted with the marketing application
“The Sponsor submitted final reports for carcinogenicity studies of fitusiran 1. A 26-week study in TgRasH2 mouse study-at3-glp17-001.pdf, 2. A 2-year study in rats study-car0186.pdf.”
hERG / QT
No hERG inhibition up to 10 μM
“Fitusiran did not inhibit hERG at up to 10μM in a GLP-compliant study.”
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)
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
Zanvastro
zilganersen · GFAP (ASO)Conducted: Ames, in vitro chromosomal aberration, mouse micronucleus; all negative