ANGPTL3 Inhibition With Evinacumab Results in Faster Clearance of IDL and LDL apoB in Patients With Homozygous Familial Hypercholesterolemia—Brief Report

Abstract

Objective: The mechanism by which evinacumab, a fully human monoclonal antibody directed against ANGPTL3 (angiopoietin-like 3 protein) lowers plasma LDL (low-density lipoprotein) cholesterol levels in patients with homozygous familial hypercholesterolemia is unknown. We investigated apoB (apolipoprotein B) containing lipoprotein kinetic parameters in patients with homozygous familial hypercholesterolemia, before and after treatment with evinacumab. Approach and Results: Four patients with homozygous familial hypercholesterolemia underwent apoB kinetic analyses in 2 centers as part of a substudy of a trial evaluating the efficacy and safety of evinacumab in patients with homozygous familial hypercholesterolemia. The enrichment of apoB with the stable isotope (5,5,5- 2 H 3 )-Leucine was measured in VLDL (very LDL), IDL (intermediate-density lipoprotein), and LDL at different time points before and after intravenous administration of 15 mg/kg evinacumab. Evinacumab lowered LDL-cholesterol by 59±2% and increased IDL apoB and LDL apoB fractional catabolic rate in all 4 homozygous familial hypercholesterolemia subjects, by 616±504% and 113±14%, respectively. VLDL-apoB production rate decreased in 2 of the 4 subjects. Conclusions: In this small study, ANGPTL3 inhibition with evinacumab is associated with an increase in the fractional catabolic rate of IDL apoB and LDL apoB, suggesting that evinacumab lowers LDL-cholesterol predominantly by increasing apoB-containing lipoprotein clearance from the circulation. Additional studies are needed to unravel which factors are determinants in this biological pathway. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04722068.

ANGPTL3 as therapeutic target

“…Consistent with this notion, changes in the lipidome of plasma lipoproteins were detected in ANGPTL3-deficient human subjects [ 45 ]. This proposed mechanism matches with data from four HoFH patients, showing that Evinacumab treatment is associated with a marked increase in fractional catabolic rate of IDL APOB [ 46 ]. Interestingly, Evinacumab treatment was also associated with an increase in fractional catabolic rate of LDL APOB, suggesting that ANGPTL3 inhibition may also directly affect LDL APOB metabolism in HoFH patients.…”

Variable Changes of Circulating ANGPTL3 and ANGPTL4 in Different Obese Phenotypes: Relationship with Vasodilator Dysfunction

“…Further studies, however, are needed to ascertain whether ANGPTL3 and ANGPTL4 play a mechanistic function in linking increased adiposity to its metabolic and vascular sequelae. Considering the efficacy shown in recent studies by therapies targeting these proteins, including antisense oligonucleotides and monoclonal antibodies [38,39], the demonstration of an involvement of ANGPTL3 and ANGPTL4 in the pathophysiology of the complications of obesity could translate into more effective, personalized strategies for prevention.…”

Targeting angiopoietin‐like 3 in atherosclerosis: From bench to bedside

“…89 explored the efficacy of evinacumab on LDL-C levels and showed that evinacumab treatment resulted in a dose-dependent reduction of LDL-C by up to 50%. 11 Similar results were obtained in patients with HoFH in a phase III randomized clinical trial, 3 in which evinacumab decreased LDL-C by inhibiting the activity of LPL and HL, but did not act on LDL-R. 10 Reeskamp et al 96 revealed that evinacumab reduced LDL-C predominantly in patients with HoFH by increasing the IDL ApoB and LDL ApoB fractional catabolic rate, which accelerated the ApoB-containing lipoprotein clearance from the circulation. Most clinical trials are registered to treat a small group of patients, and therefore the applicability of evinacumab will need to be verified in a larger population.…”