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|Objective:||To identify the optimal dose and regimen for reducing levels of triglycerides (TG) and atherogenic lipoproteins in patients with type 2 diabetes mellitus (T2DM), hepatic steatosis, and elevated TG.|
|Study design:||Multicentre, randomized, double-blind, placebo-controlled, dose-ranging, phase 2 study.Eligible patients were randomized to one of three cohorts (3:1 active to placebo treatment): subcutaneous treatment for 6 months with vupanorsen 40 mg or 80 mg every 4 weeks, or 20 mg every week.|
|Study population:||Patients with elevated fasting plasma TG (>150 mg/dL or >1.7mmol/L), T2DM and hepatic steatosis (hepatic fat fraction >8% by magnetic resonance imagining and body mass index between 27 and 40 kg/m2).|
|Main study variables:|| • Primary: per cent change in fasting TG from baseline to 6 months (Week 25 for 4-weekly dosing and Week 27 for weekly dosing) versus the pooled placebo group.
• Key secondary efficacy/exploratory endpoints: changes in fasting lipids/lipoproteins, including ANGPTL3, total cholesterol (TC), low-density lipoprotein cholesterol (LDL C), very low-density lipoprotein cholesterol (VLDL-C), remnant cholesterol, non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein (apo) B, apoCIII, apoAI; glycaemic parameters: HbA1c, Homeostatic Model Assessment of Insulin Resistance (HOMA-IR); and parameters related to hepatic steatosis
• Safety: platelet count, renal function, and liver function; adverse events
|Methods:||Pairwise comparison between each vupanorsen group and pooled placebo group was performed using an analysis of covariance (ANCOVA) model including treatment group as a fixed factor and log-transformed baseline as a covariate.|
Of 525 patients screened, 105 were randomized to vupanorsen 40 mg 4-weekly (n=26), vupanorsen 80 mg 4-weekly (n=26) and vupanorsen 20 mg weekly (n=26), versus 27 in the pooled placebo group. Overall, 93% of patients were aged less than 65 years, 47% were female, 62% were Hispanic and baseline median TG was 2.84 mmol/L (252 mg/dL).
The mean (± standard deviation) duration of treatment was 134± 41 days (median, 141) for the vupanorsen groups and 150± 35 days (median, 142) for the placebo groups. Ninety-one (87%) patients completed the study.
All three regimens of vupanorsen significantly reduced fasting TG at 6 months compared with placebo (Table 1). Placebo-corrected TG reduction was 24%, p=0.0343 for vupanorsen 40 mg 4-weekly, 44%, p<0.0001 for vupanorsen 80 mg 4-weekly, and 37%, p= 0.0009 for vupanorsen 20 mg weekly. All three regimens also significantly reduced ANGPTL3, apoCIII, remnant cholesterol, and TC. Vupanorsen 80 mg 4-weekly also significantly reduced apoB (9% reduction versus placebo, p=0.0441).
There was no improvement in glycaemic parameters, or hepatic fat fraction. Treatment with vupanorsen was not associated with clinically significant changes in platelet count. Adverse events were predominantly mild to moderate in intensity; six patients treated with vupanorsen versus none in the pooled placebo group discontinued treatment due to adverse events. Injection site reactions were reported for 16 (20.5%) patients treated with vupanorsen versus none in the pooled placebo group.
Table 1. Effect of vupanorsen on fasting TG, ANGPTL3 and atherogenic lipoproteins
|Authors’ conclusion:||Vupanorsen results in a favourable lipid/lipoprotein profile and provides a potential strategy for residual cardiovascular risk reduction.|
Conventional lipid lowering strategies do not efficiently lower plasma TG levels, leaving a residual cardiovascular risk. This provides the impetus to identify novel treatments focused on other targets relevant to TG-rich lipoprotein metabolism. One of these targets is ANGPTL3, an inhibitor of lipoprotein lipase and endothelial lipase, which are involved in the metabolism of VLDL and HDL, respectively (1). Vupanorsen is a second-generation N-acetyl galactosamine (GalNAc3)-modified antisense oligonucleotide targeting hepatic ANGPTL3 mRNA. This approach enables the antisense drug to be targeted to the asialoglycoprotein receptor on hepatocytes, thus providing similar efficacy to unconjugated agents but at 20- to 30-fold lower dosing (2)
The results of this phase 2 study show a favourable profile of efficacy and safety with this novel agent, in particular a lack of adverse effects on platelet count previously seen with volanesorsen, a non-GalNAc3 ANGPTL3 agent (3). The findings support further clinical trials with vupanorsen, in particular at higher doses in in patients with elevated TG despite statin treatment.
1. Kersten S. Angiopoietin-like3 in lipoprotein metabolism. Nat Rev Endocrinol 2017;13:731–739.
2. Crooke ST, Baker BF, Xia S, et al. Integrated assessment of the clinical performance of GalNAc3-conjugated 2’-Omethoxyethyl chimeric antisense nucleotides, I: human volunteer experience. Nucleic Acid Ther 2019;29:16–32. 3. Fogacci F, Norata GD, Toth PP, et al. Efficacy and safety of volanesorsen (ISIS 304801): the evidence from Phase 2 and
3 clinical trials. Curr Atheroscler Rep 2020;22(5):18.
|Key words||vupanorsen, angiopoietin-like 3 protein; ANGPTL3 antisense drug; triglycerides, atherogenic lipoproteins|