Amondys 45
casimersen · DMD exon 45 (PMO)In vitro only: human rhabdomyosarcoma cells and normal primary myoblasts
Redemplo: animal efficacy model or human cells?
plozasiran · APOC3 (siRNA)
Efficacy evidence
Human ApoC-III transgenic (dyslipidemic) mouse, healthy cynomolgus monkey and dyslipidemic rhesus macaque
“In vivo pharmacological characterization of plozasiran was conducted in a transgenic mouse expressing human ApoC-III (human ApoC-III mouse), healthy cynomolgus monkey, and dyslipidemic rhesus macaque monkeys.”
Why that model
Antisense strand fully complementary to monkey and human ApoC-III mRNA but has seven mismatches to rat
“The antisense strand of plozasiran is designed to be fully complementary to the monkey and human ApoC-III mRNA transcripts whereas seven sequence mismatches exist with the rat ApoC-III mRNA sequence.”
Reviewer's view of the efficacy data
EMA: in vivo PD response demonstrated by liver APOC3 suppression, lower serum APOC3 and lipid-lowering effects
“Regarding the primary pharmacology of plozasiran, it can be concluded that the in vivo PD response of plozasiran was shown by the suppression of liver APOC3 expression, reduction in serum APOC3 protein concentrations and lipid-lowering effects in serum.”
Same question, other oligonucleotides
Amvuttra
vutrisiran · TTR (siRNA)hTTR V30M transgenic mice and cynomolgus monkeys: up to >=98% serum TTR reduction
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
Hibsago
bepirovirsen · HBV RNA (ASO)Primary human hepatocytes (HBV genotype D, free uptake): HBsAg and HBeAg secretion EC50 47.1 and 29.8 nM
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
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