Amondys 45
casimersen · DMD exon 45 (PMO)Conducted; negative (Ames, CHO chromosomal aberration, mouse micronucleus)
Oxlumo: genotox, carcinogenicity and repro: done or skipped?
lumasiran · HAO1 (siRNA)
Genotoxicity
Conducted: Ames, human lymphocyte chromosome aberration, rat micronucleus; all negative
“Lumasiran was not genotoxic in an in vitro bacterial reverse mutation (Ames) assay, in vitro chromosomal aberration assay in cultured human peripheral blood lymphocytes, or in vivo micronucleus assay in rats.”
Carcinogenicity
Postmarketing requirement; later completed: 26-week Tg-rasH2 mouse and 2-year rat both negative
“Lumasiran was not carcinogenic in transgenic Tg-rasH2 mice following monthly subcutaneous administration of lumasiran for 26 weeks at doses of 150, 500, or 1500 mg/kg.”
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
Full DART: rat fertility, rat and rabbit EFD, rat PPND, plus juvenile rat study; no serious effects
“Reproductive toxicology studies did not reveal any serious fertility or teratogenic effects of lumasiran.”
Safety pharmacology
Standalone monkey CV/respiratory telemetry (10, 100 mg/kg weekly x4), no effects; CNS in 8-week monkey study
“In a standalone cardiovascular safety pharmacology study in the monkey, the administration of lumasiran at 10 and 100 mg/kg weekly for a total of four doses had no immediate or delayed effects on clinical observations, qualitative or quantitative electrocardiogram parameters,”
Genotox: Ames
Bacterial reverse mutation (Ames): negative
“Lumasiran was not genotoxic in an in vitro bacterial reverse mutation (Ames) assay, in vitro chromosomal aberration assay in cultured human peripheral blood lymphocytes, or in vivo micronucleus assay in rats.”
Genotox: in vitro mammalian
Chromosomal aberration in human peripheral blood lymphocytes: negative
“Lumasiran was not genotoxic in an in vitro bacterial reverse mutation (Ames) assay, in vitro chromosomal aberration assay in cultured human peripheral blood lymphocytes, or in vivo micronucleus assay in rats.”
Genotox: in vivo
Rat micronucleus: negative
“Lumasiran was not genotoxic in an in vitro bacterial reverse mutation (Ames) assay, in vitro chromosomal aberration assay in cultured human peripheral blood lymphocytes, or in vivo micronucleus assay in rats.”
Carcinogenicity model
26-week Tg-rasH2 mouse (up to 1500 mg/kg monthly) and rat study; not carcinogenic in mice
“Carcinogenicity studies were conducted in Tg-rasH2 mice and Sprague Dawley rats. Lumasiran was not carcinogenic in transgenic Tg-rasH2 mice following monthly subcutaneous administration of lumasiran for 26 weeks at doses of 150, 500, or 1500 mg/kg.”
Carcinogenicity timing
2-year rat and 6-month transgenic mouse studies underway at approval; postmarketing requirements
“Two-year rat and 6-month transgenic mouse carcinogenicity studies are underway. The available data do not raise concern for a risk of carcinogenicity that should delay approval given the apparent clinical benefit and unmet need. As such, these studies will be postmarketing requirements.”
hERG / QT
Monkey safety pharmacology: no QT or QTc prolongation after four SC doses of 10 and 100 mg/kg
“Safety pharmacology studies in monkeys did not demonstrate prolongation in QT or QTc (using the individual animal correction factor) after four subcutaneous doses of 10 and 100 mg/kg administered in a 3-week period.”
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
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
Zanvastro
zilganersen · GFAP (ASO)Conducted: Ames, in vitro chromosomal aberration, mouse micronucleus; all negative