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Synthesis of Monocyte-targeting Peptide Amphiphile Micelles for Imaging of Atherosclerosis
Published on: November 17, 2017
Targeting the angiopoietin-like protein 3/8 complex with a monoclonal antibody in patients with mixed hyperlipidemia:
Daniel Gaudet1, Malgorzata Gonciarz2, Xi Shen2
1Department of Medicine, Université de Montréal and ECOGENE-21, Saguenay, Quebec, Canada. daniel.gaudet@umontreal.ca.
Abstract:
The angiopoietin-like protein 3/8 complex (ANGPTL3/8) inhibits lipoprotein lipase (LPL) activity, primarily in oxidative tissues, and does so more potently than ANGPTL3, making ANPTL3/8 an attractive target for treating dyslipidemia. This study enrolled 48 adults (36 men, 12 women) with mixed hyperlipidemia to assess the primary outcome of safety and the secondary outcomes of pharmacokinetics and pharmacodynamics of ascending doses of LY3475766, a human monoclonal antibody that specifically blocks ANGPTL3/8-mediated inhibition of LPL activity. Participants received a single dose of LY3475766 or placebo. LY3475766 was well tolerated with no severe adverse events or adverse event-related discontinuations. Compared with placebo, LY3475766 dose-dependently reduced the concentration of triglycerides (-70%), remnant cholesterol (-86%), low-density lipoprotein cholesterol (-32%), non-high-density lipoprotein cholesterol (non-HDL-C) (-35%) and apolipoprotein B (-29%) while increasing HDL-C (+27%). LY3475766 thus significantly reduced atherogenic lipoprotein levels while increasing HDL-C levels; however, the effects on cardiovascular risk remain to be established. ClinicalTrials.gov registration: NCT04052594 .
Insights
A new antibody, LY3475766, effectively lowers harmful blood lipids like triglycerides and LDL cholesterol by blocking the ANGPTL3/8 complex. This offers a promising new approach for managing dyslipidemia.
Area of Science:
- Cardiovascular Medicine
- Pharmacology
- Biochemistry
Background:
- The angiopoietin-like protein 3/8 complex (ANGPTL3/8) is a potent inhibitor of lipoprotein lipase (LPL).
- Inhibition of LPL activity contributes to dyslipidemia, making ANGPTL3/8 a therapeutic target.
Purpose of the Study:
- To evaluate the safety, pharmacokinetics, and pharmacodynamics of LY3475766, a monoclonal antibody targeting ANGPTL3/8.
- To assess the effect of LY3475766 on lipid profiles in adults with mixed hyperlipidemia.
Main Methods:
- A single ascending dose study involving 48 adults with mixed hyperlipidemia.
- Participants received varying doses of LY3475766 or a placebo.
- Safety, tolerability, and lipid levels were monitored.
Main Results:
- LY3475766 was well-tolerated with no severe adverse events.
- Dose-dependent reductions were observed in triglycerides (-70%), remnant cholesterol (-86%), LDL-C (-32%), non-HDL-C (-35%), and apolipoprotein B (-29%).
- HDL-C levels increased by 27% compared to placebo.
Conclusions:
- LY3475766 demonstrates significant potential in reducing atherogenic lipoproteins and increasing HDL-C.
- Further studies are needed to establish the long-term cardiovascular risk reduction associated with LY3475766 treatment.
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