Vupanorsen in Patients With Diabetes, Hepatic Steatosis, and Hypertriglyceridemia - Vupanorsen Study

Aug 29, 2020
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Ionis Pharmaceuticals, Inc, and Akcea Therapeutics, Inc.
Date Presented:
08/29/2020
Date Published:
08/29/2020
Date Updated:
08/29/2020
Original Posted Date:
08/29/2020
References

Contribution To Literature:

Vupanorsen is superior to placebo in triglycerides and apoB-containing atherogenic lipoproteins compared with placebo among patients with DM, hepatic steatosis, and hypertriglyceridemia.

Description:

The current trial was a phase 2 trial that sought to study the safety and efficacy of vupanorsen, an antisense oligonucleotide targeting angiopoietin-like protein (ANGPTL3) mRNA in the liver.

Study Design

Patients were randomized in a 1:1:1:1 fashion to subcutaneous vupanorsen 40 mg Q4W (n = 26), vuparnosen 80 mg Q4W (n = 26), vupanorsen 20 mg QW (n = 26), or matching placebo (n = 27) for 6 months.

  • Total screened: 525
  • Total number of enrollees: 105
  • Duration of follow-up: 6 months
  • Mean patient age: 53.5 years
  • Percentage female: 47%

Inclusion criteria:

  • Elevated fasting plasma triglyceride levels (>150 mg/dl or >1.7 mmol/L)
  • Type 2 diabetes mellitus (DM) (glycated hemoglobin A1c [HbA1c] >6.5% and <+10%)
  • Hepatic steatosis (hepatic fat fraction >8% by magnetic resonance imaging)
  • Body mass index between 27 and 40 kg/m2

Exclusion criteria:

  • Type 1 diabetes mellitus
  • Active chronic liver disease, alcoholic liver disease, Wilson’s disease haemochromatosis, primary biliary cirrhosis, primary sclerosing cholangitis, genetic haemochromatosis, known or suspected hepatocellular carcinoma, history of or planned liver transplant for end-stage liver disease of any etiology
  • Documented history of advanced liver fibrosis
  • History of cirrhosis and/or hepatic decompensation including ascites, hepatic encephalopathy, or variceal bleeding
  • Uncontrolled hypertension (systolic >160 or diastolic >100 mm Hg)
  • History of acute kidney injury within 12 months of screening
  • Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed before study day 1
  • Subjects with a history of major bleed or at high risk of bleeding diathesis
  • Estimated glomerular filtration rate ˂60 ml/min/1.73 m2 (as determined by the Chronic Kidney Disease–Epidemiological Collaboration [CKD-EPI] equation)
  • Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2× upper limit of normal (ULN)
  • Bilirubin >ULN, unless prior diagnosis and documentation of Gilbert’s syndrome, in which case total bilirubin must be ≤3 mg/dl
  • Alkaline phosphatase (ALP) >1.5× ULN
  • Platelet count less than lower limit of normal

Other salient features/characteristics:

  • White: 92.4%, Hispanic: 62%
  • HbA1c: 8.2%
  • Statins: 46%, ezetimibe: 4%, fibrates: 12%
  • Baseline triglycerides 323 mg/dl, low-density lipoprotein (LDL) 100 mg/dl, high-density lipoprotein (HDL) 37 mg/dl

Principal Findings:

The primary effectiveness endpoint, change in triglycerides at 6 months from baseline for vupanorsen 40 mg Q4W vs. vuparnosen 80 mg Q4W vs. vupanorsen 20 mg QW vs. placebo, was -36% vs. -53% vs. -47% vs. -16% (p = 0.03, p < 0.0001, p = 0.0009, respectively vs. placebo).

Secondary outcomes for vupanorsen 40 mg Q4W vs. vuparnosen 80 mg Q4W vs. vupanorsen 20 mg QW vs. placebo:

  • Change in ANGPTL3 levels: -41% vs. -59% vs. -56% vs. +8% (p < 0.0001 for all)
  • Change in total cholesterol: -11% vs. -21% vs. -19% vs. -2% (p < 0.05 for all)
  • Change in LDL-C: +6% vs. -7% vs. -12% vs. 0% (p > 0.05 for all)
  • Change in HDL-C: -2% vs. -18% vs. -4% vs. +7% (p = 0.19, p < 0.0001, p = 0.11, respectively)
  • Change in HbA1c: -0.28% vs. 0.08% vs. 0.16% vs. 01.9% (p > 0.05 for all)

Safety outcomes for vupanorsen combined vs. placebo:

  • ALT between 3 and 5× ULN: 2.6% vs. 0%
  • Adverse reaction at injection site: 20.5% vs. 0%

Interpretation:

The results of this trial indicate that vupanorsen is superior to placebo in triglycerides and apolipoprotein B (apoB)-containing atherogenic lipoproteins compared with placebo among patients with DM, hepatic steatosis, and hypertriglyceridemia. This was a phase 2 trial.

ANGPTL3 is secreted by the liver, and is an inhibitor of lipoprotein lipase (LPL) and endothelial lipase (EL), two key enzymes involved in the metabolism of very LDL (VLDL) and HDL, respectively. Vupanorsen is a second-generation N-acetyl galactosamine (GalNAc3)-modified antisense oligonucleotide that targets hepatic ANGPTL3 mRNA. Vupanorsen differs from the ANGPTL3-directed monoclonal antibody evinacumab, in that the site of inhibition is in the hepatocyte, vs. the plasma with evinacumab. Similar to evinacumab, vupanorsen resulted in a lowering of HDL-C levels. However, changes in LDL-C were not meaningful in this small phase 2 trial, unlike what was observed in ELIPSE HoFH with evinacumab. The clinical relevance of these findings remains unclear.

References:

Gaudet D, Karwatowska-Prokopczuk E, Baum SJ, et al., on behalf of the Vupanorsen Study Investigators. Vupanorsen, an N-acetyl galactosamine-conjugated antisense drug to ANGPTL3 mRNA, lowers triglycerides and atherogenic lipoproteins in patients with diabetes, hepatic steatosis, and hypertriglyceridaemia. Eur Heart J 2020;41:3936-45.

Presented by Dr. Daniel Gaudet at the European Society of Cardiology Virtual Congress, August 29, 2020.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Hypertriglyceridemia, Lipid Metabolism, Nonstatins, Novel Agents

Keywords: ESC Congress, ESC20 Slides, Angiopoietins, Apolipoproteins B, Cholesterol, LDL, Diabetes Mellitus, Dyslipidemias, Fatty Liver, Hypertriglyceridemia, Lipase, Lipoproteins, Oligonucleotides, Antisense, Primary Prevention, RNA, Messenger, Triglycerides


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