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

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

"🧶Dyslipidaemias 👉CORDIOPREV trial 🇪🇸 👉Statin intolerance 👉PACMAN-AMI 👉CEPT inh 👉FOURIER-Ole 👉Regulators of TGRL: Vupanorsen; Olezarsen 👉Lp(a) in aortic stenosis" (@ValleAlfonso)

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

THE BRIGHAM PRESENTS FOUR LATE-BREAKING CLINICAL TRIALS AT ACC 2022 (Brigham Health On a Mission) - "'What we showed with bentracimab infusion is an immediate and complete reversal of ticagrelor's antiplatelet effect,' says Deepak L. Bhatt.... 'This potentially would be a drug of great interest to cardiologists and cardiac surgeons for patients who are currently being treated with ticagrelor but need emergent or urgent surgical procedures or have severe bleeding.'"

Media quote

The promising novel therapies for familial hypercholesterolemia. (PubMed, J Clin Lab Anal) - "While the therapies based on different targets including protein, RNA, and DNA are on different stages of development, the mechanisms of these novel therapies may provide new ideas for precision medicine."

Journal • Review • Atherosclerosis • Cardiovascular • Dyslipidemia • Familial Hypercholesterolemia • Gene Therapies • Genetic Disorders • Metabolic Disorders

Vupanorsen confers modest reduction in non-HDL: TRANSLATE-TIMI 70 (Healio) - "There were many interesting features of this trial. No. 1, not surprisingly, the medication lowered non-HDL and triglycerides. But what was surprising was that the reduction in apolipoprotein B was rather underwhelming and lagged behind the triglyceride and non-HDL lowering. The authors appropriately pointed out that, in a drug potentially being evaluated for CV risk reduction, this certainly causes some issues, because we know that reductions in apo B seem to be important in CV risk reduction, as well as reductions in LDL."

Media quote

Effect Of Vupanorsen On Non-high-density Lipoprotein Cholesterol Levels In Statin-treated Patients With Elevated Cholesterol - TRANSLATE-TIMI 70 (ACC 2022) - No abstract available

Clinical • Late-breaking abstract

Effect of Vupanorsen on Non-High-Density Lipoprotein Cholesterol Levels in Statin-Treated Patients With Elevated Cholesterol: TRANSLATE-TIMI 70. (PubMed, Circulation) - " Vupanorsen administered at monthly equivalent doses from 80 to 320 mg significantly reduced non-HDL-C and additional lipid parameters. Injection site reactions and liver enzyme elevations were more frequent at higher doses, and there was a dose-dependent increase in hepatic f at fraction."

Journal • Dyslipidemia • APOB

"Bescheiden effect op apoB en belangrijke veiligheidsresultaten met ASO gericht op ANGPTL3 mRNA. Lees: https://t.co/MLubYtVnoq #ACC21 #vupanorsen #ANGPTL3 #lipiden" (@CVgeneeskunde)

APOB

"#ACC22 #LBCT #TRANSLATETIMI70 @BrianBergmark Vupanorsen effect on #nonHDL 🫀Vupanorsen is 2nd gen ASO targeting ANGPTL3 mRNA 🫀1o Endpoint: % Change in nonHDL using📈 doses 💥Vupanorsen:⬇️ nonHDL dose response manner but LDL response varied" (@DrMarthaGulati)

"Pfizer and Ionis Announce Discontinuation of Vupanorsen Clinical Development Program | Pfizer https://t.co/RxhZL7EcXT #CardioTwitter #Cardiovascular #Prevention #Lipids" (@DLBHATTMD)

Clinical • Cardiovascular

"Vupanorsen reductions in ANGPTL3 of 41%, 59%, 56%, in the 40 mg Q4W, 80 mg Q4W, and 20 mg QW groups, respectively" (@drpablocorral)