Amondys 45
casimersen · DMD exon 45 (PMO)Conducted; negative (Ames, CHO chromosomal aberration, mouse micronucleus)
Izervay: genotox, carcinogenicity and repro: done or skipped?
avacincaptad pegol · C5 (aptamer)
Genotoxicity
Conducted: Ames, chromosomal aberration in mammalian cells, mouse micronucleus; all negative
“Avacincaptad pegol was negative for genotoxicity based on a standard battery of studies including the bacterial reverse mutation assay, chromosomal aberration in mammalian cells and in vivo mouse bone marrow micronucleus assays.”
Carcinogenicity
Not conducted (waiver accepted; low systemic exposure, C5-inhibitor class experience)
“Carcinogenicity No studies were conducted. The Applicant submitted a justification to support a waiver request not to conduct the carcinogenicity studies”
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
EFD studies in rat and rabbit (IV, NOAEL 1.2 mg/kg/day); FEED and PPND waived
“In the embryofetal development (EFD) toxicity studies in rats and rabbits, there was no avacincaptad pegol-related adverse effects on any measured maternal or fetal parameter at doses up to 1.2 mg/kg/day (NOAEL).”
Safety pharmacology
Dedicated: hERG assay, rat CNS study, monkey telemetry CV/respiratory (NOAEL 100 mg/kg IV); transient APTT prolongation
“The NOAEL for cardiovascular and respiratory findings in this study was the high dose, 100 mg/kg.”
Genotox: Ames
Negative
“Avacincaptad pegol was negative for genotoxicity based on a standard battery of studies including the bacterial reverse mutation assay, chromosomal aberration in mammalian cells and in vivo mouse bone marrow micronucleus assays.”
Genotox: in vitro mammalian
Chromosomal aberration in mammalian cells: negative
“Avacincaptad pegol was negative for genotoxicity based on a standard battery of studies including the bacterial reverse mutation assay, chromosomal aberration in mammalian cells and in vivo mouse bone marrow micronucleus assays.”
Genotox: in vivo
Mouse bone marrow micronucleus: negative
“Avacincaptad pegol was negative for genotoxicity based on a standard battery of studies including the bacterial reverse mutation assay, chromosomal aberration in mammalian cells and in vivo mouse bone marrow micronucleus assays.”
Carcinogenicity model
Not conducted: waiver based on mechanism of action, route, literature, class effects and existing data
“The Applicant justification to omit the conduct of nonclinical carcinogenicity studies is based on avacincaptad pegol mechanism of action, route of administration, a supportive literature review, an analysis of pharmacological class effects, and nonclinical and clinical data collected to date.”
Carcinogenicity timing
Not required: carcinogenicity waiver accepted on weight of evidence
“The Applicant submitted a justification not to conduct carcinogenicity, fertility/early embryonic development, and pre-/postnatal development studies. The Pharmacology/Toxicology team concluded that the weight of evidence supports that the studies are not necessary for the intended dosing regimen and indication.”
hERG / QT
Negative: hERG IC50 >100 µM; minimal QTc risk
“The IC50 was not determined but considered to be > 100 μM, supporting minimal risk for QTc prolongation.”
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)
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