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

Abstract

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.

Familial hypertriglyceridemia: an entity with distinguishable features from other causes of hypertriglyceridemia

“…Recent evidence has confirmed the prominent role that inhibitors of ANGPTL3 have in the removal of triglycerides-rich particles, LDL-C and apo B levels, probably due to an increased clearance of apo B containing lipoproteins and their remnants [ 33 ]. Monoclonal antibodies and antisense oligonucleotides that target ANGPTL3, and 4 are potentially an efficient therapeutic strategy for cardiovascular risk reduction in hypertriglyceridemia, especially in patients with FHTG [ 55 , 56 ]. The results suggest that this molecule may be involved in the pathogenesis of FHTG and its measurement may be helpful for diagnosis (Fig.…”

A Comprehensive Update on the Chylomicronemia Syndrome

“…Although it has been approved for use in Europe, it causes thrombocytopenia. Vupanorsen is a second generation N-acetyl galactosamine-conjugated antisense oligonucleotide derivative targeting hepatic ANGPTL3 mRNA that has greater potency allowing 20-to 30-fold lower dosing, fewer side effects and similar effects on APOC3 and triglyceride to that reported with volanesorsen (133).…”

The Interplay between Angiopoietin-Like Proteins and Adipose Tissue: Another Piece of the Relationship between Adiposopathy and Cardiometabolic Diseases?

“…A strong correlation was seen among circulating ANGPTL3 and ANGPTL8 indicating a possible co-secretion of the two proteins [ 99 , 100 ]. Recently, a phase II trial has tested vupanorsen [ 101 ], an ANGPTL3 antisense oligonucleotide, in T2DM patients [ 101 ]. Preliminary results of the study found no significant change in the HOMA index, a widely used index for insulin resistance [ 102 ].…”

“…Reported evidence might not be reliable. Morinaga et al using a self-developed and controlled ANGPTL8 assay found higher circulating levels of ANGPTL8, in T2DM patients, associated with increased levels of LDL-C, TGs, and reduced HDL-C [ 101 ]. Interestingly, differences in ANGPTL8 expression are observable in obese vs. non-obese patients: in obese patients, VAT shows increased levels of ANGPTL8 in the nucleoplasm, while serum levels remain similar to non-obese controls [ 69 ].…”

“…Preliminary results on hypertriglyceridemic patients treated with vupanorsen [ 101 ], an antisense ANGPTL3 inhibitor, did not show any significant differences in hepatic fat fraction, although levels of serum triglycerides dropped significantly [ 101 ]. The associations between ANGPTL3, lipoprotein metabolism and liver health status have been analyzed in the DiOGenes (diet, obesity, and genes) study [ 111 ].…”