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Late-Breaking Science: Lowering triglycerides with antisense oligonucleotides – are we making progress?

Given their key role in triglyceride (TG) metabolism, apolipoprotein C-III (apoC-III) and angiopoietin-like 3 (ANGPTL3) are being investigated as therapeutic targets for the treatment of hypertriglyceridaemia to reduce the residual risk of cardiovascular disease (CVD). Second-generation antisense oligonucleotides have been developed with enhanced delivery efficiency due to conjugation with N-acetyl galactosamine, which binds to a hepatocyte surface receptor for asialoglycoproteins, decreasing extra-hepatic exposure and enabling a lower dose of the antisense oligonucleotide to be administered. Late-Breaking Science presentations today described results from two phase 2 dose-ranging studies of the second-generation antisense oligonucleotides, AKCEA-APOCIII-LRx, targeted to APOC3, and AKCEA-­ANGPTL3-­LRx, targeted to ANGPTL3.  

Pharmacology and Pharmacotherapy
Coronary Artery Disease, Acute Coronary Syndromes, Acute Cardiac Care

Professor Jean-Claude Tardif (Montreal Heart Institute, Canada) described results from a trial of AKCEA­-APOCIII­-LRx vs. placebo in 114 patients with fasting serum TG levels 200–500 mg/dL (2.3–5.7 mmol/L) and established CVD or at high risk for CVD. Patients were randomised to AKCEA-­APOCIII-­LRx 10 mg or 50 mg injected subcutaneously every 4 weeks (Q4W), 15 mg every 2 weeks (Q2W), 10 mg every week (QW) or placebo.

From a median baseline fasting TG level of 262 mg/dL (2.96 mmol/L), AKCEA­-APOCIII­-LRx resulted in significant, dose-dependent reductions in the primary endpoint of percent change in fasting TG levels from baseline to 6 months compared with placebo, with a mean 62% reduction at the dose of 50 mg Q4W (p<0.0001). In total, 91% of patients treated with AKCEA-­APOCIII-­LRx 50 mg Q4W achieved a TG level ≤150 mg/dL (≤1.7 mmol/L) at 6 months, compared with 4% of patients treated with placebo (p<0.0001). Treatment also resulted in reductions in apoC­-III (up to 74%), very-low-density lipoprotein (VLDL­-C) and total cholesterol, with increased high-density lipoprotein cholesterol (HDL­-C) levels compared with placebo.

As explained by Professor Daniel Gaudet (University of Montreal, Canada), efficacy was demonstrated with AKCEA­-ANGPTL3-­LRx (vupanorsen) in a population with elevated TG and metabolic comorbidities. In total, 105 patients with fasting plasma TG levels >150 mg/dL (>1.7 mmol/L), type 2 diabetes mellitus and non-alcoholic fatty liver disease were randomised to vupanorsen 40 mg or 80 mg injected subcutaneously Q4W, 20 mg QW or placebo.

From a median baseline fasting TG level of 252 mg/dL (2.8 mmol/L), treatment with vupanorsen resulted in significant, dose­-dependent reductions in TG levels compared with placebo at all dose groups at 6 months and the highest mean reduction – 53% – was seen with 80 mg Q4W (44% percent reduction vs. placebo, p<0.0001). After 6 months, 58% of patients treated with 80 mg Q4W achieved a TG level <150 mg/dL, compared with 11% of patients treated with placebo. Vupanorsen treatment also resulted in reductions in ANGPTL3 (up to 62%), VLDL­-C, total cholesterol and non-HDL­-C vs. placebo.

In both trials, the most frequent adverse events were related to injection-site reactions and were generally of mild intensity. No clinically significant changes in platelet count were observed. The findings suggest that these second-generation antisense oligonucleotides may offer new potential possibilities to reduce residual cardiovascular risk in patients with dyslipidaemia.

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.