BACKGROUND: Patients with refractory hypercholesterolemia, who have high 
low-density lipoprotein (LDL) cholesterol levels despite treatment with 
lipid-lowering therapies at maximum tolerated doses, have an increased risk of 
atherosclerosis. In such patients, the efficacy and safety of subcutaneous and 
intravenous evinacumab, a fully human monoclonal antibody against 
angiopoietin-like 3, are not known.
METHODS: In this double-blind, placebo-controlled, phase 2 trial, we enrolled 
patients with or without heterozygous familial hypercholesterolemia who had 
refractory hypercholesterolemia, with a screening LDL cholesterol level of 70 mg 
per deciliter or higher with atherosclerosis or of 100 mg per deciliter or 
higher without atherosclerosis. Patients were randomly assigned to receive 
subcutaneous or intravenous evinacumab or placebo. The primary end point was the 
percent change from baseline in the LDL cholesterol level at week 16 with 
evinacumab as compared with placebo.
RESULTS: In total, 272 patients were randomly assigned to the following groups: 
subcutaneous evinacumab at a dose of 450 mg weekly (40 patients), 300 mg weekly 
(43 patients), or 300 mg every 2 weeks (39 patients) or placebo (41 patients); 
or intravenous evinacumab at a dose of 15 mg per kilogram of body weight every 4 
weeks (39 patients) or 5 mg per kilogram every 4 weeks (36 patients) or placebo 
(34 patients). At week 16, the differences in the least-squares mean change from 
baseline in the LDL cholesterol level between the groups assigned to receive 
subcutaneous evinacumab at a dose of 450 mg weekly, 300 mg weekly, and 300 mg 
every 2 weeks and the placebo group were -56.0, -52.9, and -38.5 percentage 
points, respectively (P<0.001 for all comparisons). The differences between the 
groups assigned to receive intravenous evinacumab at a dose of 15 mg per 
kilogram and 5 mg per kilogram and the placebo group were -50.5 percentage 
points (P<0.001) and -24.2 percentage points, respectively. The incidence of 
serious adverse events during the treatment period ranged from 3 to 16% across 
trial groups.
CONCLUSIONS: In patients with refractory hypercholesterolemia, the use of 
evinacumab significantly reduced the LDL cholesterol level, by more than 50% at 
the maximum dose. (Funded by Regeneron Pharmaceuticals; ClinicalTrials.gov 
number, NCT03175367.).