Physicians' Academy for Cardiovascular Education

Angiopoietin-like 3 antibody halves LDL-c levels in patients with refractory hypercholesterolemia

Evinacumab in patients with refractory hypercholesterolemia

Literature - Rosenson RS, Burgess LJ, Ebenbichler CF, et al. - N Engl J Med. 2020;383:2307-2319. doi: 10.1056/NEJMoa2031049. Epub 2020 Nov 15.

Introduction and methods

Patients with refractory hypercholesterolemia with or without heterozygous familial hypercholesterolemia (HeFH) have elevated levels of LDL-c despite treatment with a maximum tolerated statin, ezetimibe, and PCSK9 inhibitor. These patients have a high risk for ASCVD.

Functional analyses conducted in a phase 2 proof-of-concept study showed that evinacumab, a human monoclonal antibody directed against angiopoietin-like 3 (ANGPTL3), was effective in lowering the LDL-c concentration independent of the LDL receptor [1-3]. The phase 3 ELIPSE homozygous FH trial has previously shown that evinacumab reduced LDL-c concentrations by ~50% in patients with familiar homozygous hypercholesterolemia [4]. In both trials, evinacumab was given intravenously (IV) at a dose of 15 mg/kg bodyweight over a period of 60 minutes every 4 weeks. However, subcutaneous (SC) administration of evinacumab can be more convenient for patients.

This trial evaluated the efficacy and safety of SC and IV administration of evinacumab compared to placebo in patients with refractory hypercholesterolemia receiving polytherapy for high LDL-c plasma levels.

The trial was a randomized, double-blind, placebo-controlled phase 2 trial. Patients (18-80 years) with primary hypercholesterolemia, defined as heterozygous or non-heterozygous familial hypercholesterolemia, with clinical ASCVD were included in the study. The hypercholesterolemia was refractory to treatment of a maximum tolerated statin and PCSK9 inhibitor, with or without ezetimibe. Refractory hypercholesterolemia was defined as LDL-c levels ≥70 mg/dL (≥1.81 mmol/L) with clinical ASCVD or LDL-c ≥100 mg/dL (≥2.59 mmol/L) without clinical ASCVD. Patients were randomly assigned to SC evinacumab treatment of 450 mg weekly (n=40), 300 mg weekly (n=43), 300 mg every 2 weeks (n=39), or placebo weekly (1:1:1:1) (n=41) or IV evinacumab treatment of 15 mg/kg bodyweight every 4 weeks (n=39), 5 mg/kg bodyweight every 4 weeks (n=36), or placebo every 4 weeks (1:1:1) (n=34). Randomization was stratified according to the presence or absence of familial hypercholesterolemia (2:1) and receipt or nonreceipt to high intensity statin. The primary endpoint was the percent change from baseline in LDL-c concentration at week 16 with evinacumab compared to placebo. Secondary outcomes included lipid levels.

Main results


This phase 2 trial showed that ANGPTL3 inhibition by evinacumab in patients with refractory hypercholesterolemia, including heterozygous familial hypercholesterolemia, significantly reduced LDL-c concentrations with ~50% at maximum dose. LDL-c reduction with evinacumab at maximum dose was similar in SC and IV treated patients.


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