vupanorsen (AKCEA-ANGPTL3-LRx) / Ionis, Pfizer - LARVOL DELTA

Proteomic changes associated with vupanorsen therapy in TRANSLATE-TIMI-70 (ESC 2026) - "A targeted proteomic approach identified a set of novel protein biomarkers associated with treatment using vupanorsen and the degree of ANGPTL3 inhibition . These proteins reflect physiological pathways related to cellular response to stress, small molecule transport, lipid and heme metabolism, and immune response. Future work exploring the relationship between these proteins and the ANGPTL3 pathway is warranted."

Atherosclerosis • Cardiovascular • ANGPTL3 • FGF21 • IL4R

Promise of ANGPTL3 as a therapeutic target for controlling cholesterol levels. (PubMed, Expert Opin Ther Targets) - "These observations rapidly catalyzed the development of pharmacologic strategies to inhibit ANGPTL3 using monoclonal antibodies (e.g. evinacumab), antisense oligonucleotides (e.g. vupanorsen), small interfering ribonucleic acid (e.g. zodasiran and solbinsiran), and most recently genome-editing approaches (e.g. VERVE-201 and CTX310). The degree of hypertriglyceridemia in the patient's baseline lipid profile appears to be an important determinant of drug response. Drawing on genetic, mechanistic, and clinical trial data, the promise and limitations of ANGPTL3 inhibition are considered and its potential place in future lipid-lowering strategies is outlined."

Journal • Review • Atherosclerosis • Cardiovascular • Dyslipidemia • Familial Hypercholesterolemia • Genetic Disorders • Homozygous Familial Hypercholesterolemia • Hypertriglyceridemia • Metabolic Disorders • ANGPTL3

Effect of angiopoietin-like protein 3 inhibitors on lipid profile and other biomarkers: a meta-analysis of randomized controlled trials. (PubMed, Eur J Prev Cardiol) - "ANGPTL3 inhibition offers broad lipid-lowering benefits, with particularly marked reductions in TG-rich lipoproteins."

Biomarker • Journal • Retrospective data • Cardiovascular • Dyslipidemia • ANGPTL3 • APOA1 • APOB • APOE • CRP

RNA-Based Therapies for Hypercholesterolemia and Coronary Artery Disease. (PubMed, Cureus) - "Pelacarsen and other emerging antisense therapies show promise for reducing lipoprotein(a), an independent cardiovascular risk factor, while siRNAs targeting ANGPTL3 offer prolonged lipid-lowering effects beyond those achieved with monoclonal antibodies...Hepatic safety concerns have halted the development of some agents, such as vupanorsen, and long-term cardiovascular outcome data for several therapies, including inclisiran, are still in development. Cost and accessibility also limit broad adoption, emphasizing the need for cost-effective strategies and long-term surveillance. Nevertheless, current evidence supports the integration of RNA-based therapies into modern lipid-lowering algorithms, particularly for high-risk patients, while ongoing research continues to refine delivery systems, enhance safety, and expand therapeutic indications."

Journal • Review • Cardiovascular • Coronary Artery Disease • Dyslipidemia • Metabolic Disorders • ANGPTL3 • APOB

EFFECTS OF ANTISENSE THERAPIES TARGETING APOC3 AND ANGPTL3 ON APOC3 REDUCTION AND TRIGLYCERIDES: A META-ANALYSIS (ACC 2026) - " We conducted a meta-analysis of 11 studies evaluating antisense therapies (olezarsen, plozarsen, vupanorsen) for severe hypertriglyceridemia. Antisense therapies targeting APOC3 and ANGPTL3 yield large and consistent reductions in APOC3 and triglycerides compared to placebo. Among included agents, only plozarsen appears to demonstrate a dose-response relationship."

Retrospective data • Cardiovascular • Dyslipidemia • Hypertriglyceridemia • Severe Hypertriglyceridemia • ANGPTL3

From physiopathology to treatment of familial hypercholesterolemia: Existing and emerging pharmacotherapies. (PubMed, Pharmacol Rev) - "This includes established drugs such as proprotein convertase subtilisin/kexin type 9 inhibitors, inclisiran, lomitapide, and bempedoic acid. Emerging therapies include evinacumab, lerodalcibep, antisense oligonucleotide-based drugs, certain cholesteryl ester transfer protein inhibitors like obicetrapib, AZD8233, gemcabene, diacylglycerol O-acyltransferase-2 inhibitors, acyl-CoA:cholesterol acyltransferase-2 inhibitors, vupanorsen, volanesorsen, olezarsen, pelacarsen (TQJ230), olpasiran (AMG890), zerlasiran (SLN360), lepodisiran (LY3819469), and muvalaplin...Recent pharmacological advancements provide significant opportunities for successful low-density lipoprotein cholesterol management and control of FH. Although some of these agents are already used, several highly effective compounds are in development, heralding a promising future for FH treatment."

Journal • Review • Atherosclerosis • Cardiovascular • Dyslipidemia • Familial Hypercholesterolemia • Genetic Disorders • Metabolic Disorders • APOB

Future of angiopoietin-like protein 3 inhibitors as a therapeutic agent. (PubMed, Curr Opin Lipidol) - "ANGPTL3 inhibition offers an LDL receptor-independent means to lower atherogenic particles spanning from TRLs to LDL, complementing traditional lipid-lowering therapies. Evinacumab is practice-changing in HoFH, and RNA agents may soon broaden applicability to patients with mixed dyslipidemia and residual cardiovascular risk, pending cardiovascular outcomes trials."

Journal • Review • Atherosclerosis • Cardiovascular • Dyslipidemia • Familial Hypercholesterolemia • Genetic Disorders • Homozygous Familial Hypercholesterolemia • Metabolic Disorders • Mixed Hyperlipidemia • ANGPTL3

Effect of ANGPTL3 Inhibition on Remnant Cholesterol Subtypes (NLA 2025) - "Methods TRANSLATE-TIMI 70 was a randomized, double-blind, placebo-controlled trial of vupanorsen in patients with non-HDL-C ≥ 100 mg/dL and triglycerides 150–500 mg/dL...Conclusions Among patients with mild-to-moderate hypertriglyceridemia, the majority of RC is carried on VLDL-C, and this proportion is most pronounced at higher TG levels. Treatment of these individuals with ANGPTL3 inhibition significantly lowers RC through VLDL-C lowering only, with no effect on non-VLDL-remnant cholesterol levels."

Cardiovascular • Dyslipidemia • Genetic Disorders • Hypertriglyceridemia • Obesity • Type 2 Diabetes Mellitus • ANGPTL3

Current and Emerging Treatment Options for Hypertriglyceridemia: State-of-the-Art Review. (PubMed, Pharmaceuticals (Basel)) - "Among apolipoprotein C-III (apoC-III) inhibitors, olezarsen and plozasiran appear to be safer alternatives for volanesorsen regarding the risk of drug-induced thrombocytopenia in patients with FCS or severe HTG. After the failure of vupanorsen, a new angiopoietin-like protein 3 (ANGPTL3) inhibitor, zodasiran, demonstrated the potential to decrease TG levels in patients with moderate HTG. Meanwhile, the fibroblast growth factor 21 (FGF21) analog, pegozafermin, became another candidate for the treatment of severe HTG. This comprehensive review outlines pharmacological targets in TG-rich lipoprotein metabolism, discusses international guidelines, and summarizes the latest evidence from clinical trials to provide insight into the current and emerging treatment options for primary HTG."

Journal • Review • Atherosclerosis • Cardiovascular • Dyslipidemia • Familial Chylomicronemia Syndrome • Hematological Disorders • Hypertriglyceridemia • Metabolic Disorders • Pancreatitis • Severe Hypertriglyceridemia • Thrombocytopenia • ANGPTL3 • FGF21

A Randomized, Open-Label, Phase I, Single-Dose Study of Antisense Oligonucleotide, Vupanorsen, in Chinese Adults with Elevated Triglycerides. (PubMed, Drugs R D) - P1 | "This study provided the first clinical vupanorsen data in China. In Chinese participants with elevated TG, PK and PD parameters were consistent with those reported previously in non-Chinese participants, including in Japanese individuals. No safety concerns were noted."

Journal • Dyslipidemia • Hypertriglyceridemia • Metabolic Disorders • ANGPTL3

Gene Silencing of Angiopoietin-like 3 (ANGPTL3) Induced De Novo Lipogenesis and Lipid Accumulation in Huh7 Cell Line. (PubMed, Int J Mol Sci) - "Vupanorsen, an ANGPTL3 directed antisense oligonucleotide, showed an unexpected increase in liver fat content in humans...The effect of ANGPTL3-siRNA on the expression of genes involved in the de novo lipogenesis was not counteracted by gene silencing of PCSK9. In conclusion, our in vitro study suggests that ANGPTL3 silencing determines lipid accumulation in Huh7 cells by inducing the de novo lipogenesis independently from PCSK9."

Journal • Preclinical • Hepatology • Metabolic Disorders • Oncology • ANGPTL3 • APOB • FASN • LPL • SCD

Reductions in remnant cholesterol and VLDL cholesterol through inhibition of ANGPTL3 protein synthesis: an analysis from the TRANSLATE-TIMI 70 trial. (PubMed, Eur J Prev Cardiol) - "Inhibition of ANGPTL3 protein synthesis significantly lowered remnant cholesterol and VLDL-C in patients with hypertriglyceridaemia. The magnitude of reduction was associated with the degree of ANGPTL3 inhibition. These findings support ANGPTL3 inhibition as a promising target for lowering cholesterol on triglyceride-rich lipoproteins."

Journal • Atherosclerosis • Dyslipidemia • ANGPTL3

Advances in Dyslipidaemia Treatments: Focusing on ApoC3 and ANGPTL3 Inhibitors. (PubMed, J Lipid Atheroscler) - "Evinacumab targets ANGPTL3 and reduced LDL-C by about 50% in patients with homozygous FH and it has been approved for that indication. The antisense oligonucleotide (ASO) vupanorsen targeting ANGPTL3 was less effective in reducing LDL-C in patients with moderate hypertriglyceridaemia and its development has been discontinued but the small interfering RNA (siRNA) ARO-ANG3 is being investigated in Phase 2 studies...Olezarsen is an N-acetylgalactosamine-conjugated ASO targeting apoC3 which appears as effective as volanesorsen without the risk of thrombocytopaenia and is undergoing Phase 3 trials. ARO-APOC3 is an siRNA targeting apoC3 that is currently being investigated in Phase 3 studies."

Journal • Review • Cardiovascular • Dyslipidemia • Familial Hypercholesterolemia • Homozygous Familial Hypercholesterolemia • ANGPTL3 • LPL

Hepatic fat changes with antisense oligonucleotide therapy targeting ANGPTL3. (PubMed, J Clin Lipidol) - "Vupanorsen, an inhibitor of ANGPTL3 protein synthesis, caused dose-dependent increases in HFF. Increases in HFF were only moderately correlated with elevations in AST and ALT, suggesting that liver enzymes are an imperfect indicator to detect increases in hepatic fat. These results highlight the need to monitor HFF in clinical trials of therapies targeting intracellular ANGPTL3 inhibition, especially those that are targeted to the liver."

Journal • Diabetes • Dyslipidemia • Metabolic Disorders • ANGPTL3

ANGPTL3 Deficiency and Risk of Hepatic Steatosis. (PubMed, Circulation) - "ANGPTL3 deficiency related to LoF mutations in ANGPTL3, as well as genetically determined reduction of plasma ANGPTL3 levels, is not associated with hepatic steatosis. Therapeutic approaches to inhibit ANGPTL3 production in hepatocytes are not necessarily expected to result in the increased risk for hepatic steatosis that was observed with vupanorsen."

Journal • Dyslipidemia • ANGPTL3

Angiopoietin-like 3 inhibition and the liver: less is more? (PubMed, Curr Opin Lipidol) - "ANGPTL3 inhibition is an attractive therapeutic target to reduce all apoB-containing lipoproteins. The discrepancy in liver signal results between the antisense and siRNA approach may be explained by the level of target inhibition. An alternative explanation may relate to off-target effects of vupanorsen, which have a molecule- and/or platform-specific origin. For intrahepatic strategies, highly potent ANGPTL3 inhibition will for now require special attention for liver safety."

Journal • ANGPTL3 • APOB

Updates in Drug Treatment of Severe Hypertriglyceridemia. (PubMed, Curr Atheroscler Rep) - "The review discusses also 2 abandoned drugs for sHTG treatment, evinacumab and vupanorsen. The ASO targeting APOC3, volanesorsen, is approved for use in patients with familial chylomicronemia syndrome (FCS) in Europe. Olezarsen, an N-acetylgalactosamine (GalNAc)-conjugated ASO with the same target, seems to have a better safety and efficacy profile. siRNA targeting APOC3 and ANGPTL3, namely ARO-APOC3 and ARO-ANG3, are also promising for the treatment of sHTG. However, the ultimate clinical goal of any sHTG treatment, the decrease in the risk of AP, has not been definitively achieved till now by any pharmacotherapy, either approved or in development."

Journal • Review • Dyslipidemia • Hypertriglyceridemia • Pancreatitis • ANGPTL3

A population pharmacokinetic and pharmacokinetic-pharmacodynamic analysis of vupanorsen from phase I and phase II studies. (PubMed, CPT Pharmacometrics Syst Pharmacol) - "The developed population PK/PD model was robust to predict the dose-response relationships. The model predicted that ANGPTL3 target reduction of 75% can be sufficiently achieved with a 320-mg monthly dose of vupanorsen, but target values for TG and non-HDL-C were not expected to be achieved at doses up to 320 mg monthly in patients with dyslipidemia."

Journal • P1 data • P2 data • PK/PD data • Diabetes • Dyslipidemia • Hepatology • Hypertriglyceridemia • Metabolic Disorders • Non-alcoholic Fatty Liver Disease

A multi-purpose Japanese phase I study in the global development of vupanorsen: Randomized, placebo-controlled, single-ascending dose study in adults. (PubMed, Clin Transl Sci) - P1 | "Moreover, the SAD study in Japanese participants fulfilled PMDA bridging requirements, and with the totality of global vupanorsen data, supported the PMDA waiver for a local phase II dose-finding study. ClinicalTrials.gov: NCT04459767."

Clinical • Journal • P1 data • Dyslipidemia • Hypertriglyceridemia • Metabolic Disorders

HEPATIC FAT CHANGES AFTER AN ANTISENSE OLIGONUCLEOTIDE THERAPY TARGETING ANGPTL3: A TRANSLATE-TIMI 70 ANALYSIS (ACC-WCC 2023) - "Vupanorsen caused increases in HFF that were associated with dose and with the degree of ANGPTL3 inhibition even after adjusting for dosing regimen. These findings suggest that hepatic fat will be important to evaluate for future therapies targeting ANGPTL3, especially those that work intracellularly."

Diabetes • Metabolic Disorders

Lipid metabolism and the targeting of angiopoietin-like 3: Experimental drugs under development. (PubMed, Expert Opin Investig Drugs) - No abstract available

Journal • Cardiovascular • Dyslipidemia • Metabolic Disorders

How ANGPTL3 Inhibition Will Help Our Clinical Practice? (PubMed, Curr Atheroscler Rep) - "Finally, we will examine the lipid-lowering potential of pharmacological inhibition of ANGPTL3 based on the results of clinical trials employing Evinacumab, the first approved fully humanized monoclonal antibody against ANGPTL3. The future perspectives for ANGPTL3 inhibition will also be revised."

Journal • Review • Cardiovascular • Dyslipidemia • Familial Hypercholesterolemia • Genetic Disorders • Homozygous Familial Hypercholesterolemia • Metabolic Disorders • LPL

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Dyslipidemia

Recent Advances in Gene Therapy for Familial Hypercholesterolemia: An Update Review. (PubMed, J Clin Med) - "Various RNA-targeted therapies are in phase 1-3 clinical trials, such as small interfering RNA-based drugs inclisiran, ARO-ANG3, ARO-APOC3, olpasiran, SLN360, and antisense oligonucleotide-based drugs AZD8233, vupanorsen, volanesorsen, IONIS-APO(a)Rx, etc., all of which have demonstrated excellent lipid-lowering effects. With gene editing technologies, such as CRISPR-Cas 9 and meganuclease, completing animal experiments in mice or cynomolgus monkeys and demonstrating lasting lipid-lowering effects, patients with FH are expected to reach a permanent cure in the future. (4) Gene therapy is being widely used for the lipid-lowering treatment of FH patients and has shown excellent therapeutic promise, but the current delivery efficiency, economic burden, immunogenicity and the precision of gene therapy can be further optimized."

Journal • Review • Dyslipidemia • Familial Hypercholesterolemia • Gene Therapies • Genetic Disorders • Homozygous Familial Hypercholesterolemia • Metabolic Disorders

Angiopoietin-like 3: An important protein in regulating lipoprotein levels. (PubMed, Best Pract Res Clin Endocrinol Metab) - "The identification of ANGPTL3 deficiency as a cause of familial combined hypolipidemia in humans hastened the development of anti-ANGPTL3 therapeutic agents, including evinacumab (a monoclonal antibody inhibiting circulating ANGPTL3), vupanorsen (an antisense oligonucleotide [ASO] targeting hepatic ANGPTL3 mRNA for degradation), and others. Here, we review the discovery of ANGPTL3 as an important regulator of lipoprotein metabolism, molecular characteristics of the protein, mechanisms by which it regulates plasma lipids, and the clinical development of anti-ANGPTL3 agents. The clinical success of therapies inhibiting ANGPTL3 highlights the importance of this target as a novel approach in treating refractory hypertriglyceridemia and hypercholesterolemia."

Journal • Review • Cardiovascular • Dyslipidemia • Hypertriglyceridemia • Metabolic Disorders