scholarly journals ANGPTL3 Inhibition With Evinacumab Results in Faster Clearance of IDL and LDL apoB in Patients With Homozygous Familial Hypercholesterolemia

2021 ◽  
Author(s):  
Laurens F. Reeskamp ◽  
John S. Millar ◽  
Liya Wu ◽  
Hans Jansen ◽  
Dewi van Harskamp ◽  
...  
Keyword(s):  
Familial Hypercholesterolemia ◽  
Ldl Cholesterol ◽  
Low Density Lipoprotein ◽  
Human Monoclonal Antibody ◽  
Density Lipoprotein ◽  
Fractional Catabolic Rate ◽  
Homozygous Familial Hypercholesterolemia ◽  
Unique Identifier ◽  
Catabolic Rate ◽  
Before And After

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.

Abstract 14270: The Effect of Evinacumab on Apheresis Eligibility in Patients With Homozygous Familial Hypercholesterolemia

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Frederick J Raal ◽  
Robert S Rosenson ◽  
Laurens F Reeskamp ◽  
G. Kees Hovingh ◽  
John J Kastelein ◽  
...  
Keyword(s):  
Familial Hypercholesterolemia ◽  
Low Density Lipoprotein ◽  
Human Monoclonal Antibody ◽  
Density Lipoprotein ◽  
Lipid Lowering ◽  
Atherosclerotic Cardiovascular Disease ◽  
Homozygous Familial Hypercholesterolemia ◽  
Double Blind ◽  
Lipid Disorder ◽  
Artery Disease

Background: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic lipid disorder characterized by elevated low-density lipoprotein cholesterol (LDL-C) levels and premature atherosclerotic cardiovascular disease. Evinacumab, a fully human monoclonal antibody against angiopoietin-like protein 3, has demonstrated approximately 50% reductions in LDL-C in HoFH patients when added to maximally tolerated lipid-lowering therapies. Objective: In this post-hoc analysis, we assessed the effect of evinacumab on the eligibility for apheresis using predefined US and EU apheresis criteria. Methods: This was a double-blind, placebo-controlled, 24-week phase 3 trial (NCT03399786) that randomized patients 2:1 to evinacumab 15 mg/kg intravenously every 4 weeks (Q4W; n=43) or placebo (n=22). We assessed the proportion of patients who met per protocol US apheresis criteria (LDL-C ≥300 mg/dL), newer US criteria for FH (LDL-C ≥300 mg/dL or LDL-C ≥160 mg/dL with coronary heart disease or peripheral artery disease) and per protocol EU apheresis criteria (LDL-C >160 mg/dL [primary prevention] or >120 mg/dL [secondary prevention]) at baseline and week 24. Results: Under the newer US criteria (2018), 62.8% (n=27) of evinacumab-treated patients and 54.5% (n=12) placebo-treated patients qualified for apheresis at baseline (Table). Following 24 weeks of treatment, 48.8% of all evinacumab versus 9.1% of all placebo patients no longer qualified for apheresis. Similar results were observed using EU apheresis criteria, where 46.5% of evinacumab-treated patients shifted from qualifying for apheresis at baseline to not qualifying at week 24, compared with 4.5% of placebo-treated patients. The majority of evinacumab (65.1%) and placebo (68.2%) patients did not qualify for per protocol US apheresis at baseline, however a shift of 27.9% and 9.1% was observed, respectively. Conclusions: Evinacumab has the potential to reduce the need for apheresis in patients with HoFH.

scholarly journals Galactose-specific asialoglycoprotein receptor is involved in lipoprotein (a) catabolism

2003 ◽  
Vol 376 (3) ◽  
pp. 765-771 ◽  
Author(s):  
Andelko HRZENJAK ◽  
Sasa FRANK ◽  
Xingde WO ◽  
Yonggang ZHOU ◽  
Theo van BERKEL ◽  
...  
Keyword(s):  
Physiological Function ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Asialoglycoprotein Receptor ◽  
Fractional Catabolic Rate ◽  
Wild Type ◽  
Lipoprotein A ◽  
Apolipoprotein A ◽  
Catabolic Rate ◽  
First Time

Lp(a) [lipoprotein (a)] is a highly atherogenic plasma lipoprotein assembled from low-density lipoprotein and the glycoprotein apolipoprotein (a). The rate of Lp(a) biosynthesis correlates significantly with plasma Lp(a) concentrations, whereas the fractional catabolic rate does not have much influence. So far, little is known about Lp(a) catabolism. To study the site and mode of Lp(a) catabolism, native or sialidase-treated Lp(a) was injected into hedgehogs or ASGPR (asialoglycoprotein receptor)-knockout (ASGPR−) mice or wild-type (ASGPR+) mice, and the decay of the plasma Lp(a) concentration was followed. COS-7 cells were transfected with high- (HL-1) and low-molecular-mass ASGPR subunits (HL-2), and binding and degradation of intact or desialylated Lp(a) were measured. In hedgehogs, one of the few species that synthesize Lp(a), most of the Lp(a) was taken up by the liver, followed by kidney and spleen. Lp(a) and asialo-Lp(a) were catabolized with apparent half-lives of 13.8 and 0.55 h respectively. Asialo-orosomucoide increased both half-lives significantly. In mice, the apparent half-life of Lp(a) was 4–6 h. Catabolism of native Lp(a) by wild-type mice was significantly faster compared with ASGPR− mice and there was a significantly greater accumulation of Lp(a) in the liver of ASGPR+ mice compared with ASGPR− mice. The catabolism of asialo-Lp(a) in ASGPR− mice was 8-fold faster when compared with native Lp(a) in wild-type mice. Transfected COS-7 cells expressing functional ASGPR showed approx. 5-fold greater binding and 2-fold faster degradation of native Lp(a) compared with control cells. Our results for the first time demonstrate a physiological function of ASGPR in the catabolism of Lp(a).

Oxidative structural modifications of low density lipoprotein in homozygous familial hypercholesterolemia

1995 ◽  
Vol 118 (2) ◽  
pp. 259-273 ◽  
Author(s):  
Claudio Napoli ◽  
Alfredo Postiglione ◽  
Massimo Triggiani ◽  
Gaetano Corso ◽  
Giuseppe Palumbo ◽  
...  
Keyword(s):  
Familial Hypercholesterolemia ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Density ◽  
Homozygous Familial Hypercholesterolemia ◽  
Structural Modifications
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