Amvuttra
vutrisiran · TTR (siRNA)Conducted: Ames, human lymphocyte chromosome aberration, rat micronucleus; all negative
Amondys 45: genotox, carcinogenicity and repro: done or skipped?
casimersen · DMD exon 45 (PMO)
Genotoxicity
Conducted; negative (Ames, CHO chromosomal aberration, mouse micronucleus)
“Casimersen was tested in a standard battery of in vitro (bacterial reverse mutation, chromosomal aberration in CHO cells) and in vivo (mouse micronucleus) genetic toxicology assays. The studies were adequately conducted and negative.”
Carcinogenicity
Not conducted pre-approval (deferred to PMR); Tg mouse and rat dose-ranging studies done
“Carcinogenicity assessments are deferred to post-marketing for the DMD indication.”
Reproductive & developmental
Not conducted (patients extremely rare in females); male reproductive endpoints in tox studies; juvenile rat
“Reproductive and developmental toxicology studies were not required because of the intended patient population (extremely rare in females), and carcinogenicity studies may be conducted post-approval”
Safety pharmacology
Standalone monkey CV/neurological study (4 weekly IV doses up to 320 mg/kg) plus hERG; no adverse effects
“Cynomolgus monkeys received IV injections of SRP-4045 weekly for 4 total doses of 0, 5, 40, or 320 mg/kg.”
Genotox: Ames
Negative
“Casimersen was negative in in vitro (bacterial reverse mutation assay and chromosomal aberration assay in CHO cells) and in vivo (mouse bone marrow micronucleus) assays.”
Genotox: in vitro mammalian
Chromosomal aberration in CHO cells: negative
“Casimersen was negative in in vitro (bacterial reverse mutation assay and chromosomal aberration assay in CHO cells) and in vivo (mouse bone marrow micronucleus) assays.”
Genotox: in vivo
Mouse bone marrow micronucleus: negative
“Casimersen was negative in in vitro (bacterial reverse mutation assay and chromosomal aberration assay in CHO cells) and in vivo (mouse bone marrow micronucleus) assays.”
Carcinogenicity model
26-week Tg.rasH2 mouse (SC) and up to 104-week rat (IV); no increase in neoplasms
“Administration of casimersen to male transgenic (Tg.rasH2) mice (0, 100, 300, or 1000 mg/kg) weekly for 26 weeks by subcutaneous injection and to male rats (0, 125, 250, or 500 mg/kg) for up to 104 weeks by intravenous injection resulted in no increase in neoplasms.”
Carcinogenicity timing
Mouse and rat carcinogenicity studies deferred to postmarketing requirements; not conducted before approval
“Carcinogenicity assessments were not conducted. PMRs covering the carcinogenicity assessments are recommended.”
hERG / QT
hERG IC50 >3 mM
“The ICso for the inhibitory effect of SRP-4045 on the hERG current was greater than 3 mM.”
Same question, other oligonucleotides
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)
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