N-acetyl galactosamine-conjugated antisense drug to APOC3 mRNA, triglycerides and atherogenic lipoprotein levels

Abstract

Aims: Elevated apolipoprotein C-III (apoC-III) levels are associated with hypertriglyceridaemia and coronary heart disease. AKCEA-APOCIII-LRx is an N-acetyl galactosamine-conjugated antisense oligonucleotide targeted to the liver that selectively inhibits apoC-III protein synthesis.

Methods and results: The safety, tolerability, and efficacy of AKCEA-APOCIII-LRx was assessed in a double-blind, placebo-controlled, dose-escalation Phase 1/2a study in healthy volunteers (ages 18-65) with triglyceride levels ≥90 or ≥200 mg/dL. Single-dose cohorts were treated with 10, 30, 60, 90, and 120 mg subcutaneously (sc) and multiple-dose cohorts were treated with 15 and 30 mg weekly sc for 6 weeks or 60 mg every 4 weeks sc for 3 months. In the single-dose cohorts treated with 10, 30, 60, 90, or 120 mg of AKCEA-APOCIII-LRx, median reductions of 0, -42%, -73%, -81%, and -92% in apoC-III, and -12%, -7%, -42%, -73%, and -77% in triglycerides were observed 14 days after dosing. In multiple-dose cohorts of 15 and 30 mg weekly and 60 mg every 4 weeks, median reductions of -66%, -84%, and -89% in apoC-III, and -59%, -73%, and -66% in triglycerides were observed 1 week after the last dose. Significant reductions in total cholesterol, apolipoprotein B, non-high-density lipoprotein cholesterol (HDL-C), very low-density lipoprotein cholesterol, and increases in HDL-C were also observed. AKCEA-APOCIII-LRx was well tolerated with one injection site reaction of mild erythema, and no flu-like reactions, platelet count reductions, liver, or renal safety signals.

Conclusion: Treatment of hypertriglyceridaemic subjects with AKCEA-APOCIII-LRx results in a broad improvement in the atherogenic lipid profile with a favourable safety and tolerability profile. ClinicalTrials.gov Identifier: NCT02900027.

Keywords: Antisense; Apolipoprotein C-III; Cardiovascular disease; Hypertriglyceridaemia.

© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.

Figures

Figure 1

Single ascending dose cohorts. The graphs display the mean percent change (±SEM) in apoC-III (A), triglycerides (B), apoB (C), and HDL-C (D) in the single dose cohorts. The blue arrowhead represents the timing of the dose. The data were compared between AKCEA-APOCIII-LRx treatments and placebo using one-way analysis of variance or Wilcoxon rank sum test. Subjects were required to have a fasting triglyceride level ≥90 mg/dL for the 10, 30, and 60 mg dose cohorts and ≥200 mg/dL for the 90 and 120 mg cohorts.

Figure 2

Multiple ascending dose cohorts. The graphs display the mean percent change (±SEM) in apoC-III (A), triglycerides (B), apoB (C), and HDL-C (D) in the multiple dose cohorts. The blue arrowhead represents the timing of the doses. The data were compared between AKCEA-APOCIII-LRx treatments and placebo using one-way analysis of variance or Wilcoxon rank sum test. Subjects were required to have a fasting triglyceride level ≥200 mg/dL.

Figure 3

Every 4-week dosing multiple dose cohorts. The graphs display the mean percent change (±SEM) in apoC-III (A), triglycerides (B), apoB (C), and HDL-C (D) in the every 4-week multiple dose cohorts. The blue arrowhead represents the timing of the doses. The data were compared between AKCEA-APOCIII-LRx treatments and placebo using one-way analysis of variance or Wilcoxon rank sum test. Subjects were required to have a fasting triglyceride level ≥200 mg/dL.

Take home figure

Panel (A) represents the size and density patterns of HDL, LDL, and VLDL particles. Each of the particles is shown containing variable amounts of apoC-III. The relative proportion and locations of total cholesterol, HDL-C, LDL-C, and VLDL-C, and apoB are shown in a stylized tube of ultracentrifugally prepared lipoproteins (B). The effect of APOCIII-LRx on these lipoproteins are shown on the right (C) with significant reductions in triglycerides, VLDL-C, LDL-C, and increases in HDL-C. IDL and chylomicrons are not shown in this figure as the subjects were fasting. The numbers in the illustration are derived from the 30 mg/weekly dose measured at 1 week after the last dose.