Amondys 45
casimersen · DMD exon 45 (PMO)In vitro only: human rhabdomyosarcoma cells and normal primary myoblasts
Zanvastro: animal efficacy model or human cells?
zilganersen · GFAP (ASO)
Efficacy evidence
Transgenic mice overexpressing human GFAP (AxD-like features reduced); species surrogate ASO in rat AxD model
“Specifically, administration of zilganersen reduced GFAP mRNA and AxD-like features in transgenic mice overexpressing human GFAP; additionally, a species surrogate ASO reduced brain GFAP mRNA and decreased GFAP protein in the CSF of a rat model of AxD.”
Why that model
No cross-reactivity to rodent or monkey GFAP mRNA, so human GFAP transgenic mice used
“Given the lack of cross-reactivity to rodent or monkey GFAP mRNA, pharmacologic effects of zilganersen in vivo were evaluated in”
Reviewer's view of the efficacy data
FDA: target engagement and mechanistic data confirmed biologic plausibility of the treatment benefit
“These target engagement and mechanistic data confirmed the biologic plausibility of the observed treatment benefit and that the drug is having its intended effect.”
Same question, other oligonucleotides
Amvuttra
vutrisiran · TTR (siRNA)hTTR V30M transgenic mice and cynomolgus monkeys: up to >=98% serum TTR reduction
Cyfendus
anthrax vaccine adsorbed, adjuvanted · TLR9 (CpG 7909 adjuvant)Guinea pig and cynomolgus macaque lethal aerosolized B. anthracis spore challenge after two IM vaccinations
Dawnzera
donidalorsen · Prekallikrein / KLKB1 (ASO)Mouse-specific surrogate ASO ISIS 482584 in five in vivo mouse vascular permeability studies
Defitelio
defibrotide · Fragmented DNA oligonucleotidesIn vitro studies, primarily in a human microvascular endothelial cell line
Exondys 51
eteplirsen · DMD exon 51 (PMO)Exon 51 skipping in human muscle cell cultures, DMD patient muscle explants, transgenic hDMD mice (IM) and cynomolgus monkey (IV)
Givlaari
givosiran · ALAS1 (siRNA)Mouse and rat AIP disease models: givosiran prevented and reduced phenobarbital-induced ALA and PBG
Heplisav-B
hepatitis B vaccine (recombinant), adjuvanted · TLR9 (CpG 1018 adjuvant)Anti-HBsAg immunogenicity of the adjuvanted vaccine in mice, rats and baboons
Izervay
avacincaptad pegol · C5 (aptamer)In vitro and ex vivo complement functional assays plus in vivo complement inhibition in monkey
Kynamro
mipomersen · APOB (ASO)Species-specific surrogate apoB ASOs in mouse, hamster, rabbit and monkey lipid models (mouse atherosclerosis models)
Leqvio
inclisiran · PCSK9 (siRNA)PCSK9/LDL-C lowering in human PCSK9 transgenic mice and healthy NHPs
Macugen
pegaptanib · VEGF-165 (aptamer)Mouse retinopathy of prematurity (hypoxia-induced retinal neovascularization), rat corneal pocket angiogenesis, guinea pig dermal permeability
Onpattro
patisiran · TTR (siRNA)V30M/Hsf-1 KO mouse disease model (ALN-TTR01, same siRNA): 97-100% tissue TTR protein suppression
Oxlumo
lumasiran · HAO1 (siRNA)Genetic PH1 mouse model (AGXT-/-): dose-dependent urinary oxalate reduction (~50% at 3 mg/kg)
Qalsody
tofersen · SOD1 (ASO)Clinical molecule in transgenic human SOD1G93A mice and rats: SOD1 mRNA reduction; improved lifespan and rotarod in mouse
Qfitlia
fitusiran · Antithrombin / SERPINC1 (siRNA)Hemophilia A and B knockout mice, genetic hemophilia A dog and antibody-induced hemophilia A monkey
Redemplo
plozasiran · APOC3 (siRNA)Human ApoC-III transgenic (dyslipidemic) mouse, healthy cynomolgus monkey and dyslipidemic rhesus macaque
Rivfloza
nedosiran · LDHA (siRNA)PH1 (Agxt knockout) and hydroxyproline-induced mouse models with mouse-active analog DCR-m355; LDHA knockdown in monkeys
Rytelo
imetelstat · Telomerase (oligo)Xenograft mice with ovarian cancer and AML cell lines and paediatric AML patient-derived cells
Spinraza
nusinersen · SMN2 (ASO)Transgenic SMA mouse models expressing human SMN2 (ICV and IT dosing)
Tegsedi
inotersen · TTR (ASO)Transgenic mouse expressing human TTR Ile84Ser mutation and cynomolgus monkey (TTR mRNA/protein lowering)
Tryngolza
olezarsen · APOC3 (ASO)Human apoC-III transgenic mice, wild-type CD-1 mice (mouse surrogate) and cynomolgus monkeys; primary hepatocytes in vitro
Viltepso
viltolarsen · DMD exon 53 (PMO)DMD patient fibroblasts differentiated into myotubes: exon 53 skipping (EC50 0.63-2.3 µM) and dystrophin production
Vitravene
fomivirsen · CMV IE2 mRNA (ASO)In vitro HCMV inhibition in primary human retinal pigment epithelial (RPE) cells
Vyondys 53
golodirsen · DMD exon 53 (PMO)Rhabdomyosarcoma cells and immortalized and primary myoblasts from DMD patients; no in vivo exon 53 skipping study with golodirsen
Wainua
eplontersen · TTR (ASO)Human mutant TTR (I84S) transgenic mice: hepatic hTTR mRNA and plasma TTR reduction
Waylivra
volanesorsen · APOC3 (ASO)Fructose-fed hypertriglyceridemic rhesus monkeys dosed with volanesorsen (binding site 100% homologous)