What question did this study set out to answer?

To evaluate the safety, pharmacodynamics, and lipid-lowering effects of antisense oligonucleotides targeting ANGPTL3 mRNA in preclinical mouse models and human participants.

May 24, 2017New England Journal of MedicineOpen Access

Cardiovascular and Metabolic Effects of ANGPTL3 Antisense Oligonucleotides

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Why the study?

Does an antisense oligonucleotide targeting ANGPTL3 mRNA reduce atherogenic lipoproteins in humans with elevated triglycerides?

Population

44 human participants with triglyceride levels of either 90 to 150 mg/dL or >150 mg/dL, and a preclinical…

Comparison

Subcutaneous injections of an antisense… vs Subcutaneous injections of placebo.

Design

RCT, randomly assigned

Follow-up

6 weeks

Authors

MGMark J. GrahamPreventive Cardiology RLRichard LeeGeneral / Preventive / Lipids TBTeresa BrandtAcadia Pharmaceuticals (United States)

Discussion

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Implication

Establishes proof-of-concept for ANGPTL3 mRNA inhibition to lower atherogenic lipoproteins.

Key Points

To evaluate the safety, pharmacodynamics, and lipid-lowering effects of antisense oligonucleotides targeting ANGPTL3 mRNA in preclinical mouse models and human participants.
Evaluated antisense oligonucleotides (ASOs) targeting Angptl3 mRNA in mice to assess lipid levels, triglyceride clearance, hepatic triglyceride content, insulin sensitivity, and atherosclerosis progression.
Conducted a randomized trial (NCT02709850) in 44 human participants receiving subcutaneous placebo or ANGPTL3 ASOs as single doses (20, 40, or 80 mg) or multiple weekly doses (10, 20, 40, or 60 mg) for 6 weeks.
In mice, Angptl3 ASOs caused dose-dependent reductions in hepatic Angptl3 mRNA, protein, triglycerides, and LDL cholesterol, while retarding atherosclerosis progression and increasing insulin sensitivity.
In humans, 6 weeks of multiple-dose ASO treatment lowered ANGPTL3 protein by 46.6% to 84.5% (P<0.01 for all doses vs. placebo), triglycerides by 33.2% to 63.1%, LDL cholesterol by 1.3% to 32.9%, and VLDL cholesterol by 27.9% to 60.0%.
Dizziness or headache occurred in 3 participants receiving the ASO and 3 receiving placebo, with no serious adverse events observed.

Structured PICO

Does an antisense oligonucleotide targeting ANGPTL3 mRNA reduce atherogenic lipoproteins in humans with elevated triglycerides?

Population

44 human participants with triglyceride levels of either 90 to 150 mg/dL (1.0 to 1.7 mmol/L) or >150 mg/dL, and a preclinical mouse model.

Intervention

Subcutaneous injections of an antisense oligonucleotide targeting ANGPTL3 mRNA in a single dose (20, 40, or 80 mg) or multiple doses (10, 20, 40, or 60 mg per week for 6 weeks).

Comparator

Subcutaneous injections of placebo.

Outcome

Safety, side-effect profile, pharmacokinetic and pharmacodynamic measures, and changes in levels of lipids and lipoproteins.surrogate

Antisense oligonucleotides targeting ANGPTL3 mRNA safely and significantly reduced levels of atherogenic lipoproteins, including triglycerides and LDL cholesterol, in humans.

Cite This Study

Graham et al. (2017) studied this question.

synapsesocial.com/papers/6a7d01662f2f9d79738b19bf https://doi.org/10.1056/nejmoa1701329

Topics

Coronary artery disease Lipid management

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Cardiovascular and Metabolic Effects of ANGPTL3 Antisense Oligonucleotides

Discussion

Member takes

Implication

Key Points

Structured PICO

Cite This Study

Topics

Cardiovascular and Metabolic Effects of ANGPTL3 Antisense Oligonucleotides

Discussion

Member takes

Implication

Key Points

Structured PICO

Cite This Study

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