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.”
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
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.”
Genotox: Ames
Negative (Ames)
“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.”
Genotox: in vitro mammalian
Chromosomal aberration in TK6 lymphoblastoid cells: negative
“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.”
Genotox: in vivo
Mouse micronucleus: negative
“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 model
26-week transgenic (Tg.rasH2) mouse completed; 2-year rat study to follow postmarketing
“The carcinogenic potential of plozasiran was assessed in the completed 26-week transgenic mouse carcinogenicity study. The Agency agreed that a 2-year rat carcinogenicity study should be conducted postmarketing considering the unmet medical need associated with the FCS clinical indication.”
Carcinogenicity timing
26-week rasH2 mouse completed; 2-year rat ongoing at approval, completion to be submitted postmarketing
“The 2-year rat carcinogenicity study is ongoing, and the Agency recommends that completion of this study should be submitted postmarketing (after approval) considering the unmet medical need associated with the FCS clinical indication.”
hERG / QT
No effect on hERG tail current at 6.4 μM (100 μg/mL); large margin to human unbound Cmax
“At a concentration of 6.4 μM (100 μg/mL), plozasiran did not affect hERG tail current amplitude in vitro. This represents a large safety margin to the human unbound Cmax (15.6 ng/mL) at the proposed therapeutic dose.”
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
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