Amondys 45
casimersen · DMD exon 45 (PMO)Juvenile rat no-effect dose (300 mg/kg) ~4x human AUC at 30 mg/kg/week
Spinraza: what safety margin did regulators accept?
nusinersen · SMN2 (ASO)
Safety margin at NOAEL
No margin: monkey 53-week neurotoxicity no-effect dose 0.3 mg gave CSF 12 ng/mL, within patient levels (7-35 ng/mL)
“The no-effect dose (0.3 mg) for neurotoxicity in the 53-week monkey study was associated with csf levels (12 ng/mL) generally less than that in SMA patients (7-35 ng/mL); therefore, there is no safety margin based on csf levels.”
NOAEL / key findings
Monkey neurotoxicity NOAEL 0.3 mg/dose; hippocampal neuronal vacuolation/necrosis; no CSF-based safety margin
“The no-effect dose (0.3 mg) for neurotoxicity in the 53-week monkey study was associated with csf levels (12 ng/mL) generally less than that in SMA patients (7-35 ng/mL); therefore, there is no safety margin based on csf levels.”
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
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
Defitelio
defibrotide · Fragmented DNA oligonucleotidesNot 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