TY - JOUR
T1 - ANGPTL3 Inhibition with Evinacumab Results in Faster Clearance of IDL and LDL apoB in Patients with Homozygous Familial Hypercholesterolemia - Brief Report
AU - Reeskamp, Laurens F.
AU - Millar, John S.
AU - Wu, Liya
AU - Jansen, Hans
AU - van Harskamp, Dewi
AU - Schierbeek, Henk
AU - Gipe, Daniel A.
AU - Rader, Daniel J.
AU - Dallinga-Thie, Geesje M.
AU - Hovingh, G. Kees
AU - Cuchel, Marina
N1 - Publisher Copyright: © 2021 Cambridge University Press. All rights reserved.
PY - 2021/5
Y1 - 2021/5
N2 - 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 (5,5,5-2H3)-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.
AB - 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 (5,5,5-2H3)-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.
KW - angiopoietin-like protein
KW - cholesterol, LDL
KW - familial hypercholesterolemia
KW - isotope
KW - leucine
KW - lipoprotein
UR - http://www.scopus.com/inward/record.url?scp=85104752357&partnerID=8YFLogxK
U2 - https://doi.org/10.1161/ATVBAHA.120.315204
DO - https://doi.org/10.1161/ATVBAHA.120.315204
M3 - Article
C2 - 33691480
SN - 1079-5642
VL - 41
SP - 1753
EP - 1759
JO - Arteriosclerosis, Thrombosis, and Vascular Biology
JF - Arteriosclerosis, Thrombosis, and Vascular Biology
IS - 5
ER -