Amondys 45
casimersen · DMD exon 45 (PMO)Juvenile rat no-effect dose (300 mg/kg) ~4x human AUC at 30 mg/kg/week
Defitelio: what safety margin did regulators accept?
defibrotide · Fragmented DNA oligonucleotides
Safety margin at NOAEL
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.
NOAEL / key findings
13-week rat: adverse findings in kidneys, liver and lymphoid tissues; prolonged PT (rat) and APTT (rat and dog)
“Target organs of toxicity were identified in a 13-week rat toxicology study, which included adverse findings in the kidneys, liver and lymphoid tissues. Defibrotide also prolonged prothrombin time (PT) in rats, in addition to activated partial thromboplastin time (APTT) in rats and dogs.”
Same question, other oligonucleotides
Amvuttra
vutrisiran · TTR (siRNA)NOAELs (150 mg/kg rat, 300 mg/kg monkey monthly) ~600x and ~4400x human AUC at 25 mg Q3M
Dawnzera
donidalorsen · Prekallikrein / KLKB1 (ASO)Monkey NOAEL 6 mg/kg/wk: ~29x (monthly) and ~58x (Q8W) clinical exposure
Exondys 51
eteplirsen · DMD exon 51 (PMO)Low: NOAEL exposure 3.4x human in monkey and <1x in mdx mouse (surrogate); highest doses 17-20x
Givlaari
givosiran · ALAS1 (siRNA)No adverse findings at 3.5-fold (rat) and 26.3-fold (monkey) the exposure at the maximum recommended human dose
Heplisav-B
hepatitis B vaccine (recombinant), adjuvanted · TLR9 (CpG 1018 adjuvant)Monkey NOAEL 0.5 mg/kg CpG adjuvant, >10-fold the clinical mg/kg dose, for systemic immunostimulation
Izervay
avacincaptad pegol · C5 (aptamer)Dog intravitreal NOAEL 1.0 mg/eye = 0.66x the recommended clinical dose
Kynamro
mipomersen · APOB (ASO)Monkey chronic (12-month) NOAEL 10 mg/kg/week approximates clinical exposure at 200 mg/wk (body surface area)
Leqvio
inclisiran · PCSK9 (siRNA)NOAEL ~48.9x (rat) and ~99.6x (monkey) human AUC at 300 mg; 99x/101x by Cmax
Macugen
pegaptanib · VEGF-165 (aptamer)Rat IV NOAEL plasma concentration ~240x human Cmax at 3 mg/eye
Oxlumo
lumasiran · HAO1 (siRNA)Rat NOAEL 200 mg/kg ~44x and monkey NOAEL 300 mg/kg ~150x human AUC
Qalsody
tofersen · SOD1 (ASO)Monkey 9-month IT NOAEL 12 mg (HED 120 mg) ~1.2x the 100 mg human dose by CSF-volume scaling
Qfitlia
fitusiran · Antithrombin / SERPINC1 (siRNA)Monkey 39-week top dose 0.5 mg/kg/week (tolerated) is below the MRHD on a BSA dose basis
Redemplo
plozasiran · APOC3 (siRNA)Monkey NOAEL 180 mg/kg Q4W (highest dose): 140-fold MRHD by BSA
Rivfloza
nedosiran · LDHA (siRNA)Juvenile monkey NOAEL 100 mg/kg: AUC ~29-fold human exposure
Rytelo
imetelstat · Telomerase (oligo)Mouse NOAEL 2.4x and monkey HNSTD 28.1x human exposure at recommended dose
Spinraza
nusinersen · SMN2 (ASO)No margin: monkey 53-week neurotoxicity no-effect dose 0.3 mg gave CSF 12 ng/mL, within patient levels (7-35 ng/mL)
Tegsedi
inotersen · TTR (ASO)AUC margins at NOAELs for monkey thrombocytopenia and rat kidney toxicity ≤ ~2-fold
Tryngolza
olezarsen · APOC3 (ASO)Monkey NOAEL 6 mg/kg/wk ~6x MRHD (80 mg/month) by BSA
Vyondys 53
golodirsen · DMD exon 53 (PMO)Juvenile rat NOAEL 100 mg/kg ~2.6x human plasma exposure at 30 mg/kg
Wainua
eplontersen · TTR (ASO)Monkey NOAEL 134x human AUC (112x Cmax) at 45 mg
Zanvastro
zilganersen · GFAP (ASO)Monkey NOAEL 5x, mouse 17x the proposed 50 mg dose (CSF-volume-normalized dose)
Cyfendus
anthrax vaccine adsorbed, adjuvanted · TLR9 (CpG 7909 adjuvant)Not stated in public reviews
Onpattro
patisiran · TTR (siRNA)Not stated in public reviews
Viltepso
viltolarsen · DMD exon 53 (PMO)Not stated in public reviews
Vitravene
fomivirsen · CMV IE2 mRNA (ASO)Not stated in public reviews
Waylivra
volanesorsen · APOC3 (ASO)Not stated in public reviews