Antisense to ANGPLT3 reduces TG and atherogenic lipoproteins

Vupanorsen, an N-acetyl Galactosamide-conjugated Antisense drug to ANGPTL3 mRNA, lowers triglycerides and atherogenic lipoproteins in patients with diabetes, hepatic steatosis and hypertriglyceridemia.

Presented at ESC Congress 2020 by Daniel Gaudet (Montreal, QC, Canada)

Introduction and methods

ANGPTL3 is an inhibitor of lipoprotein lipase (LPL) and endothelial lipase (EL) and secreted by the liver. Loss-of-function mutations in ANGPTL3 are associated with a phenotype called familial combined hypolipidemia and affected individuals have reduced triglyceride (TG) and triglyceride-rich lipoproteins (TRL) levels, decreased plasma LDL particles clearance, and increased insulin sensitivity and approximately 40% lower risk of CAD compared to non-carriers. Preclinical studies have shown that lowering of ANGPLT3 results in decreased extent of atherosclerosis.

Vupanorsen (AKCEA-ANGPTL3-LRx) is an antisense oligonucleotide targeting hepatic ANGPLT3 mRNA and a second generation GalNAc3-conjugated antisense oligonucleotide with enhanced intracellular uptake in hepatocytes, allowing lower dosing (compared to first generation compounds).

This was a multicenter, double-blind, placebo-controlled, dose-ranging phase 2 study. It enrolled T2DM patients with hepatic steatosis, and fasting TG levels >150 mg/dL. 105 Patients were included in 3 cohorts with different dosing strategy and within cohort they were randomized to vupanorsen or placebo (ratio 3:1) for a treatment period of 6 months. Primary endpoint was mean percentage change in fasting TG from baseline to 6 months in each cohort.

Main results

• TG least squares mean % change was 16% in the pooled placebo group, -36% in the 40 mg Q4W group (P=0.03), -53% in the 80 mg Q4W group (P<0.0001), and -47% in the 20 mg QW group (P=0.0009).
• Secondary endpoints of % change in ANGPTL3, TC, VLDL-c, nonHDL-c and ApoC-III were significantly greater in groups who received vuparnorsen compared to placebo.
• There were no effects of vupanorsen on glycemic control or hepatic steatosis markers.
• Injection site reactions were the most frequent treatment emergent adverse events (TEAEs). Any TEAEs occurred in 59.3% in the pooled placebo group and ranged from 73.1% to 88.5% in the vuparnorsen groups. TEAEs leading to discontinuation occurred ranged from 3.8% to 11.5% in the vuparnosen groups (none in the placebo group).
• There were no effects of vupanorsen on platelet count, liver function markers and renal function markers compared to placebo.

Conclusions

Reducing ANGPTL3 levels with vupanorsen in T2DM patients with hepatic steatosis and mild hypertriglyceridemia resulted in reduction of plasma TG levels, as well as significant reduction in other apoB-containing atherogenic lipoproteins. Vupanorsen had a favorable safety and tolerability profile. The authors suggest that vuparnosen may provide a new strategy for reduction of residual CV risk.

- Our reporting is based on the information provided at the ESC congress 2020 -