Amondys 45
casimersen · DMD exon 45 (PMO)In vitro only: human rhabdomyosarcoma cells and normal primary myoblasts
Onpattro: animal efficacy model or human cells?
patisiran · TTR (siRNA)
Efficacy evidence
V30M/Hsf-1 KO mouse disease model (ALN-TTR01, same siRNA): 97-100% tissue TTR protein suppression
“In a mouse disease model (the V30M/Hsf-1 KO mouse model), the tissue TTR protein suppression is 97-100% after 6 doses of ALN-TTR01 (LNP with same siRNA as patisiran-LNP) at 3mg/kg (bi-weekly; only one dose was tested).”
Why that model
siRNA targets human TTR mRNA; cross-reacts with cynomolgus monkey but not rat, mouse or rabbit
“Patisiran is a siRNA directed against human TTR mRNA and has cross-reactivity in the cynomolgus monkeys, but not in rat mouse or rabbit.”
Reviewer's view of the efficacy data
EMA: unclear whether inhibition is equal for all TTR variants, but in vitro IC50 similar (~16-36 pM) across five common mutations
“While it is not clear if the patisiran inhibition effect is the same for all possible TTR polymorphisms, the in-vitro inhibition range for the five more common human transthyretin disease-linked polymorphisms (V30M, T60A, S77Y, S77F, and V122I) is relatively similar at an IC50 between ~16pM and 36pM.”
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
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)
Zanvastro
zilganersen · GFAP (ASO)Transgenic mice overexpressing human GFAP (AxD-like features reduced); species surrogate ASO in rat AxD model