Targeting apolipoprotein C-III (apoC-III) mRNA may reduce the residual cardiovascular (CV) risk in patients with hypertriglyceridaemia and either established cardiovascular disease (CVD) or high CV risk. This was suggested by the findings of the phase 2 AKCEA-APOCIII-LRx study, which showed that treatment with this compound resulted in dose-dependent reductions of apoC-III, triglyceride levels, and other atherogenic lipoproteins compared with placebo .
Hypertriglyceridaemia is associated with severely increased CV risk in patients who, despite maximal treatment with lipid-lowering therapies, retain elevated lipid profiles. ApoC-III is a crucial regulator of the hepatic uptake of triglyceride-rich lipoproteins and plasma triglyceride levels. In addition, apoC-III may exert pro-atherogenic effects by enhancing vessel wall inflammation. As such, targeting apoC-III is an attractive approach to ameliorate excess triglyceride-rich lipoproteins, such as seen in patients with hypertriglyceridaemia. Indeed, loss-of-function germline mutation in the APOC3 gene results in reduced levels of triglycerides and triglyceride-rich lipoproteins, increased HDL-cholesterol, and approximately 40% reduction of CVD compared with non-carriers. Epidemiologic studies have demonstrated that apoC-III levels predict CV risk.
Prof. Jean-Claude Tardif (University of Montréal, Canada) presented the placebo-controlled, dose-ranging, phase 2 AKCEA-APOCIII-LRx study. AKCEA-APOCIII-LRx is an antisense oligonucleotide targeting hepatic APOC3 mRNA. It is a second-generation GalNAc3-conjugated antisense oligonucleotide that enhances the intracellular hepatic uptake compared with unconjugated antisense oligonucleotides, allowing lower dosing. Eligible patients had fasting triglyceride levels of 200-500 mg/dL and either established CVD or high CV risk. Participants (n=114) were randomised into 4 parallel cohorts with AKCEA-APOCIII-LRx in different dosing strategies or placebo. The primary endpoint was the mean percentage change in fasting triglyceride levels from baseline to 6 months.
While there was no significant change in triglyceride levels in the placebo group (+6%), there were significant dose-related reductions in triglyceride levels in the AKCEA-APOCIII-LRx groups compared with the pooled placebo group, namely:
- -23% in 10 mg Q4W group (P=0.004);
- -56%, in 15 mg Q2W (P<0.0001);
- -60% in 10 mg QW (P<0.0001); and
- -60% in 50 mg Q4W (P<0.0001).
The percentage of patients who had triglyceride levels <150 mg/dL at 6 months were as follows:
- 4% in the placebo group;
- 14% in 10 mg Q4W group (P=0.2590);
- 65% in 15 mg Q2W (P<0.0001);
- 76% in 10 mg QW (P<0.0001); and
- 91% in 50 mg Q4W (P<0.0001).
The percentage change in secondary endpoints apoC-III, VLDL-c, and non-HDL-cholesterol showed significant dose-dependent reductions with AKCEA-APOCIII-LRx as well as increases in HDL-cholesterol and ApoA1 with AKCEA-APOCIII-LRx compared with placebo.
The incidence of treatment-emergent adverse events (TEAE) was 83.3% in the pooled placebo group and ranged from 77.3% to 95.7% in the AKCEA-APOCIII-LRx treated groups. TEAEs leading to discontinuation did not change between placebo and AKCEA-APOCIII-LRx arms. There were no clinically significant effects on platelet counts, liver function, or kidney function by AKCEA-APOCIII-LRx.
Treatment with AKCEA-APOCIII-LRx resulted in dose-dependent reductions in apoC-III in up to 74% of patients and in dose-dependent reductions of triglyceride levels in up to 62% of patients compared with placebo. In addition, this compound showed favourable safety and tolerability profile. These results suggest that targeting APOC3 mRNA may reduce the residual CV risk in patients with hypertriglyceridaemia.
- Tardif J-C. Antisense oligonucleotide targeting apolipoprotein C-III (AKCEA-APOCIII-LRx) to lower triglycerides and atherogenic lipoproteins in patients with hypertriglyceridemia and cardiovascular disease. Lipids session, ESC Congress 2020, 29 Aug.
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Table of Contents: ESC 2020
Letter from the Editor
ESC 2020 Highlights Podcast
2020 ESC Clinical Practice Guidelines
2020 Atrial Fibrillation Guidelines
2020 Non-ST-Segment Elevation Acute Coronary Syndromes Guidelines
2020 Sports Cardiology and Exercise in Cardiovascular Patients Guidelines
2020 Adult Congenital Heart Disease Guidelines
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