ISIS-ANGPTL3RX, an antisense inhibitor to angiopoietin-like 3, reduces plasma lipid levels in mouse models and in healthy human volunteers

Brandt, Teresa; Lee, R.G.; Digenio, Andrés; Ma, Guoyi; Crooke, Rosanne M.; Hughes, Steve; Singleton, W. S.; Witztum, Joseph L.; Tsimikas, Sotirios

doi:10.1016/j.atherosclerosis.2015.04.115

Cited by 13 publications

(8 citation statements)

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“…In line with the animal data, treatment with ANGPTL3 ASO (also referred to as Vupanorsen) significantly reduced plasma ANGPTL3, triglyceride, LDL-C, and HDL-C levels in two phase 1 trials in healthy adults, with the magnitude of the decrease depending on the dose and frequency of the injections [ 29 , 31 ]. In a recent phase 2 trial in type 2 diabetes patients with hepatic steatosis and hypertriglyceridemia, ANGPTL3 ASO compared with placebo significantly and dose-dependently decreased plasma triglycerides to a maximum of 53%.…”

Section: Pharmacological Strategies For Angptl3 Inactivationmentioning

confidence: 76%

ANGPTL3 as therapeutic target

Kersten

2021

Current Opinion in Lipidology

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Purpose of review Elevated LDL-C and triglycerides are important risk factors for the development of atherosclerotic cardiovascular disease. Although effective therapies for lipid lowering exist, many people do not reach their treatment targets. In the last two decades, ANGPTL3 has emerged as a novel therapeutic target for lowering plasma LDL-C and triglycerides. Here, an overview of the recent literature on ANGPTL3 is provided, focusing on the therapeutic benefits of inactivation of ANGPTL3 via monoclonal antibodies, antisense oligonucleotides, and other more nascent approaches. In addition, the potential mechanisms by which ANGPTL3 inactivation lowers plasma LDL-C are discussed. Recent findings ANGPTL3 is a factor secreted by the liver that inhibits lipoprotein lipase and other lipases via the formation of a complex with the related protein ANGPTL8. Large-scale genetic studies in humans have shown that carriers of loss-of-function variants in ANGPTL3 have lower plasma LDL-C and triglyceride levels, and are at reduced risk of atherosclerotic cardiovascular disease. Clinical studies in patients with different forms of dyslipidemia have demonstrated that inactivation of ANGPTL3 using monoclonal antibodies or antisense oligonucleotides markedly lowers plasma LDL-C and triglyceride levels. Summary Anti-ANGPTL3 therapies hold considerable promise for reducing plasma LDL-C and triglycerides in selected patient groups.

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Section: Pharmacological Strategies For Angptl3 Inactivationmentioning

confidence: 76%

ANGPTL3 as therapeutic target

Kersten

2021

Current Opinion in Lipidology

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“…Although a prior non-GalNAc ANGPTL3 ASO was studied in phase 1 at doses up to 400 mg weekly 13 vupanorsen has ∼30-fold higher potency and can be administered at a markedly lower dose at a less frequent dosing interval. Vupanorsen also differs from the ANGPTL3-directed monoclonal antibody evinacumab, in that the site of inhibition is in the hepatocyte, vs. the plasma with evinacumab.…”

Section: Discussionmentioning

confidence: 99%

Vupanorsen, an N-acetyl galactosamine-conjugated antisense drug to ANGPTL3 mRNA, lowers triglycerides and atherogenic lipoproteins in patients with diabetes, hepatic steatosis, and hypertriglyceridaemia

Gaudet

Karwatowska‐Prokopczuk

Baum

et al. 2020

European Heart Journal

206

160

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Aims Loss-of-function mutations in ANGPTL3 are associated with beneficial effects on lipid and glucose metabolism and reduced risk of coronary artery disease. Vupanorsen (AKCEA-ANGPTL3-L Rx ) is an N-acetyl galactosamine-conjugated antisense oligonucleotide targeted to the liver that selectively inhibits angiopoietin-like 3 (ANGPTL3) protein synthesis. Methods and results This was a double-blind, placebo-controlled, dose-ranging, Phase 2 study. Patients (N =105) with fasting triglycerides >150 mg/dL (>1.7 mmol/L), type 2 diabetes, and hepatic steatosis were treated for 6 months with 40 or 80 mg every 4 weeks (Q4W), or 20 mg every week (QW) of vupanorsen, or placebo given subcutaneously. The primary efficacy endpoint was per cent change in fasting triglycerides from baseline at 6 months. Median baseline triglycerides were 2.84 mmol/L (252 mg/dL). Significant reductions in triglycerides of 36%, 53%, 47%, and in ANGPTL3 of 41%, 59%, 56%, were observed in the 40 mg Q4W, 80 mg Q4W, and 20 mg QW groups, respectively, compared with 16% reduction in triglycerides and 8% increase in ANGPTL3 in placebo. Compared with placebo, vupanorsen 80 mg Q4W reduced apolipoprotein C-III (58%), remnant cholesterol (38%), total cholesterol (19%), non-high-density lipoprotein cholesterol (HDL-C; 18%), HDL-C (24%), and apolipoprotein B (9%). There was no improvement in glycaemic parameters, or hepatic fat fraction. Treatment with vupanorsen was not associated with clinically significant changes in platelet counts, and the most common adverse events were those at the injection site, which were generally mild. Conclusion Vupanorsen results in a favourable lipid/lipoprotein profile and provides a potential strategy for residual cardiovascular risk reduction.

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“…Although modest effects of the antisense oligonucleotide were seen in normocholesterolemic mice, potent reductions in plasma TG (up to 88%) and cholesterol (up to 66%) along with reduced atherosclerosis were seen in LDLr −/− mice [143]. In a Phase I study, ISIS-ANGPTL3 Rx showed an acceptable safety profile and dose-dependent reductions in plasma ANGPTL3 (82%), TG (49%) and total cholesterol (28%) [143]. Patients with higher baseline TGs showed a higher reduction in plasma TGs.…”

Section: Pharmacological Targeting Of Lplmentioning

confidence: 99%

Emerging strategies of targeting lipoprotein lipase for metabolic and cardiovascular diseases

Geldenhuys

Darvesh

et al. 2017

Drug Discovery Today

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Although statins and other pharmacological approaches have improved the management of lipid abnormalities, there exists a need for newer treatment modalities especially for the management of hypertriglyceridemia. Lipoprotein lipase (LPL), by promoting hydrolytic cleavage of the triglyceride core of lipoproteins, is a crucial node in the management of plasma lipid levels. Although LPL expression and activity modulation is observed as a pleiotropic action of some the commonly used lipid lowering drugs, the deliberate development of drugs targeting LPL has not occurred yet. In this review, we present the biology of LPL, highlight the LPL modulation property of currently used drugs and review the novel emerging approaches to target LPL.

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ISIS-ANGPTL3RX, an antisense inhibitor to angiopoietin-like 3, reduces plasma lipid levels in mouse models and in healthy human volunteers

Cited by 13 publications

References 0 publications

ANGPTL3 as therapeutic target

ANGPTL3 as therapeutic target

Vupanorsen, an N-acetyl galactosamine-conjugated antisense drug to ANGPTL3 mRNA, lowers triglycerides and atherogenic lipoproteins in patients with diabetes, hepatic steatosis, and hypertriglyceridaemia

Emerging strategies of targeting lipoprotein lipase for metabolic and cardiovascular diseases

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