Evinacumab for Homozygous Familial Hypercholesterolemia

N Engl J Med. 2020 Aug 20;383(8):711-720. doi: 10.1056/NEJMoa2004215.


Background: Homozygous familial hypercholesterolemia is characterized by premature cardiovascular disease caused by markedly elevated levels of low-density lipoprotein (LDL) cholesterol. This disorder is associated with genetic variants that result in virtually absent (null-null) or impaired (non-null) LDL-receptor activity. Loss-of-function variants in the gene encoding angiopoietin-like 3 (ANGPTL3) are associated with hypolipidemia and protection against atherosclerotic cardiovascular disease. Evinacumab, a monoclonal antibody against ANGPTL3, has shown potential benefit in patients with homozygous familial hypercholesterolemia.

Methods: In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned in a 2:1 ratio 65 patients with homozygous familial hypercholesterolemia who were receiving stable lipid-lowering therapy to receive an intravenous infusion of evinacumab (at a dose of 15 mg per kilogram of body weight) every 4 weeks or placebo. The primary outcome was the percent change from baseline in the LDL cholesterol level at week 24.

Results: The mean baseline LDL cholesterol level in the two groups was 255.1 mg per deciliter, despite the receipt of maximum doses of background lipid-lowering therapy. At week 24, patients in the evinacumab group had a relative reduction from baseline in the LDL cholesterol level of 47.1%, as compared with an increase of 1.9% in the placebo group, for a between-group least-squares mean difference of -49.0 percentage points (95% confidence interval [CI], -65.0 to -33.1; P<0.001); the between-group least-squares mean absolute difference in the LDL cholesterol level was -132.1 mg per deciliter (95% CI, -175.3 to -88.9; P<0.001). The LDL cholesterol level was lower in the evinacumab group than in the placebo group in patients with null-null variants (-43.4% vs. +16.2%) and in those with non-null variants (-49.1% vs. -3.8%). Adverse events were similar in the two groups.

Conclusions: In patients with homozygous familial hypercholesterolemia receiving maximum doses of lipid-lowering therapy, the reduction from baseline in the LDL cholesterol level in the evinacumab group, as compared with the small increase in the placebo group, resulted in a between-group difference of 49.0 percentage points at 24 weeks. (Funded by Regeneron Pharmaceuticals; ELIPSE HoFH ClinicalTrials.gov number, NCT03399786.).

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Angiopoietin-Like Protein 3
  • Angiopoietin-like Proteins / antagonists & inhibitors*
  • Antibodies, Monoclonal / adverse effects
  • Antibodies, Monoclonal / blood
  • Antibodies, Monoclonal / therapeutic use*
  • Anticholesteremic Agents / adverse effects
  • Anticholesteremic Agents / blood
  • Anticholesteremic Agents / therapeutic use*
  • Child
  • Cholesterol, LDL / blood*
  • Double-Blind Method
  • Female
  • Homozygote
  • Humans
  • Hyperlipoproteinemia Type II / blood
  • Hyperlipoproteinemia Type II / drug therapy*
  • Hyperlipoproteinemia Type II / genetics
  • Infusions, Intravenous
  • Least-Squares Analysis
  • Male
  • Middle Aged
  • Mutation
  • Receptors, LDL / metabolism
  • Young Adult


  • ANGPTL3 protein, human
  • Angiopoietin-Like Protein 3
  • Angiopoietin-like Proteins
  • Antibodies, Monoclonal
  • Anticholesteremic Agents
  • Cholesterol, LDL
  • Receptors, LDL
  • evinacumab

Associated data

  • ClinicalTrials.gov/NCT03399786