Apolipoprotein C-III reduction in subjects with moderate hypertriglyceridaemia and at high cardiovascular risk

Abstract

Aims: Hypertriglyceridaemia is associated with increased risk of cardiovascular events. This clinical trial evaluated olezarsen, an N-acetyl-galactosamine-conjugated antisense oligonucleotide targeted to hepatic APOC3 mRNA to inhibit apolipoprotein C-III (apoC-III) production, in lowering triglyceride levels in patients at high risk for or with established cardiovascular disease.

Methods and results: A randomized, double-blind, placebo-controlled, dose-ranging study was conducted in 114 patients with fasting serum triglycerides 200-500 mg/dL (2.26-5.65 mmol/L). Patients received olezarsen (10 or 50 mg every 4 weeks, 15 mg every 2 weeks, or 10 mg every week) or saline placebo subcutaneously for 6-12 months. The primary endpoint was the percent change in fasting triglyceride levels from baseline to Month 6 of exposure. Baseline median (interquartile range) fasting triglyceride levels were 262 (222-329) mg/dL [2.96 (2.51-3.71) mmol/L]. Treatment with olezarsen resulted in mean percent triglyceride reductions of 23% with 10 mg every 4 weeks, 56% with 15 mg every 2 weeks, 60% with 10 mg every week, and 60% with 50 mg every 4 weeks, compared with increase by 6% for the pooled placebo group (P-values ranged from 0.0042 to <0.0001 compared with placebo). Significant decreases in apoC-III, very low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B were also observed. There were no platelet count, liver, or renal function changes in any of the olezarsen groups. The most common adverse event was mild erythema at the injection site.

Conclusion: Olezarsen significantly reduced apoC-III, triglycerides, and atherogenic lipoproteins in patients with moderate hypertriglyceridaemia and at high risk for or with established cardiovascular disease.

Trial registration number: NCT03385239.

Keywords: Antisense; Atherosclerosis; Cardiovascular disease; Cardiovascular risk factors; Hypertriglyceridaemia; apoC-III.

Structured Graphical Abstract

Potential clinical indications for olezarsen. Triglyceride levels represent a continuum of risk with levels 1.7–5.6 mmol/L (150–500 mg/dL) representing primarily cardiovascular disease risk (cardiovascular disease prevention), levels between 5.6 and 10.0 mmol/L (500–885 mg/dL) representing both cardiovascular disease and pancreatitis risk and >10.0 mmol/L primarily pancreatitis risk in patients with familial chylomicronemia syndrome and multifactorial chylomicronemia syndrome (represented by milky plasma). Treatment with olezarsen with the planned Phase 3 doses of 50 and 80 mg subcutaneously monthly would be expected to substantially reduce triglyceride levels in the entire continuum of hypertriglyceridaemia.

Figure 1

Effect of olezarsen on fasting triglyceride levels. (A) The least squares mean percent changes in triglycerides from baseline to the primary analysis timepoint. (B) The temporal changes in triglycerides in each of the dose groups. Error bars denote 95% confidence interval. Primary analysis timepoint was Week 27 for weekly dosing, and Week 25 for monthly dosing. The least squares mean of percent change from baseline (95% confidence interval) in each treatment group and the P-value of each olezarsen treatment group vs. the pooled placebo group were estimated using an ANCOVA model with the treatment group as the fixed factor and log-transformed baseline value as the covariate.

Figure 2

The least squares mean percent changes in apolipoprotein C-III, total cholesterol, very-low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, apolipoprotein B, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol from baseline to the primary analysis timepoint. Error bars denote 95% confidence interval. primary analysis timepoint was Week 27 for weekly dosing, and Week 25 for monthly dosing.

Figure 3

Percent of patients achieving fasting triglyceride levels <150 mg/dL (<1.7 mmol/L) (A) and <100 mg/dL (<1.13 mmol/L) (B) at the primary analysis timepoint. The P-values of each olezarsen treatment group vs. the pooled placebo group were estimated using a logistic regression model with the treatment group as the fixed factor and log-transformed baseline value as the covariate.