Amondys 45
casimersen · DMD exon 45 (PMO)Conducted; negative (Ames, CHO chromosomal aberration, mouse micronucleus)
Spinraza: genotox, carcinogenicity and repro: done or skipped?
nusinersen · SMN2 (ASO)
Genotoxicity
Conducted; negative (Ames, CHO chromosomal aberration, mouse micronucleus)
“ISIS 396443 was negative in an adequately conducted standard battery of in vitro (Ames and chromosomal aberration in CHO) and in vivo (mouse micronucleus) assays.”
Carcinogenicity
Not conducted pre-approval (IT route infeasible); SC carcinogenicity study as postmarketing requirement
“Carcinogenicity studies have not been conducted with nusinersen at this time. The Division has recommended that a carcinogenicity study be conducted after approval.”
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
Mouse fertility/EFD and rabbit EFD (SC): no clear toxicity; PPND ongoing as PMR
“No clear evidence of reproductive or developmental toxicity was seen in mouse and rabbit studies, and ISIS 396443 was negative for genotoxicity in a standard battery of in vitro and in vivo assays.”
Safety pharmacology
Rat IT-infusion respiratory/CV study; CNS endpoints incorporated into monkey IT tox studies
“Safety pharmacology consisted of a respiratory and cardiovascular safety pharmacology study in rats treated by continuous intrathecal (IT) infusion.”
Genotox: Ames
Negative (Ames)
“ISIS 396443 was negative in an adequately conducted standard battery of in vitro (Ames and chromosomal aberration in CHO) and in vivo (mouse micronucleus) assays.”
Genotox: in vitro mammalian
Chromosomal aberration in CHO cells: negative
“ISIS 396443 was negative in an adequately conducted standard battery of in vitro (Ames and chromosomal aberration in CHO) and in vivo (mouse micronucleus) assays.”
Genotox: in vivo
Mouse micronucleus: negative
“ISIS 396443 was negative in an adequately conducted standard battery of in vitro (Ames and chromosomal aberration in CHO) and in vivo (mouse micronucleus) assays.”
Carcinogenicity model
2-year SC mouse study: increased vascular tumors (hemangioma/hemangiosarcoma) at the highest dose
“Administration of nusinersen (0, 5, 15, or 50 mg/kg) to male and female mice by subcutaneous injection, once every two weeks for 2 years, resulted in an increase in the incidence of vascular tumors (combined hemangioma and hemangiosarcoma) at the highest dose tested.”
Carcinogenicity timing
No carcinogenicity study before approval; 2-year carcinogenicity study is a postmarketing requirement
“the sponsor should conduct a 2-year carcinogenicity study as a postmarketing requirement.”
hERG / QT
No ECG effects in repeat-dose IT monkey studies; no cardiovascular effects in rats with 25-day IT infusion
“In safety pharmacology studies, there were no pulmonary or cardiovascular effects in rats using continuous intrathecal (IT) infusion for 25 days, or effects on ECG in the repeat-dose IT toxicology studies in monkeys.”
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)
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