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.