Evinacumab Lowers LDL Cholesterol in Refractory Hypercholesterolemia

ASCVD CHD Risk Familial Hypercholesterolemia
ASCVD CHD Risk Familial Hypercholesterolemia
In this phase 2 trial, patients with hypercholesterolemia and clinical atherosclerotic cardiovascular disease were recruited from 85 sites across 20 countries.

Evinacumab therapy significantly reduced low-density lipoprotein cholesterol (LDL-c) concentrations by up to 50% among patients with refractory hypercholesterolemia. These findings, from a double-blind, placebo-controlled, phase 2 trial, were published in the New England Journal of Medicine.

Patients (N=266) with hypercholesterolemia and clinical atherosclerotic cardiovascular disease were recruited from 85 sites across 20 countries. This study included both subcutaneous (450 mg weekly [n=40], 300 mg weekly [n=42], 300 mg every 2 weeks [n=39], or placebo weekly [n=41] for 16 weeks) and intravenous (15 mg/kg [n=39], 5 mg/kg [n=36], or placebo [n=34] every 4 weeks for 6 months) therapies, in which status of heterozygous familial hypercholesterolemia was factored into the randomization scheme. LDL-c levels and safety were assessed at the study’s conclusion.

Respectively, the subcutaneous and intravenous participants at baseline had heterozygous familial hypercholesterolemia (72% and 81%), the mean LDL-c was 150.0 plus or minus 80.2 and 144.5 plus or minus 54.0 mg/dl, 44% and 52% were receiving high-intensity statins, and 30% and 38% were receiving ezetimibe. The patients who were randomly assigned to receive 300 mg of subcutaneous evinacumab every 2 weeks had lower baseline LDL-c (136.2±70.2 mg/dl) than participants from other groups.

Among the subcutaneous recipients, at 16 weeks the change from baseline of LDL-c was -47.2% (450 mg) and -44.0% (300 mg/week), and the placebo group had an 8.8% change. Compared with placebo, the 450-mg dose had the greatest difference (-56.0%; 95% CI, -73.7% to -38.3%; P <.001) followed by the 300-mg/weekly dose (-52.9%; 95% CI, -70.7% to -35.1%; P <.001) and the 300-mg/every 2 weeks treatment (-38.5%; 95% CI, -56.5% to -20.6%; P <.001).

Among the group receiving intravenous treatment, at 16 weeks the change from baseline was -49.9% among the 15-mg group compared with a 0.6% change for the placebo cohort. This difference equated to a -50.5% (95% CI, -68.4% to -32.6%; P <.001) difference among the high-dose group. The difference between the 5-mg dose and placebo was -24.2% (95% CI, -42.6% to -5.7%).

Adverse events were experienced by 68% (450 mg), 67% (300 mg/week), and 82% (300 mg/every 2-weeks) of those on the subcutaneous regimen; 54% receiving subcutaneous placebo; and 84% (15 mg/kg) and 75% (5 mg/kg) of those on the intravenous regimen, and 70% receiving the intravenous placebo. The events that were more frequent among subcutaneous treatment recipients were urinary tract infections, injection-site erythema, arthralgia, and myalgia. Among intravenous treatment recipients, the most common events were nasopharyngitis, bodily pain, fatigue, nausea, and dizziness.

Few major adverse events led to treatment discontinuation (evinacumab: n=6; placebo: n=3). Two evinacumab recipients died during the study from heart failure or cardiogenic shock (300 mg/week) and sudden cardiac death (300 mg/every 2 weeks). No significant safety differences between subcutaneous and intravenous therapies were found.

This study was limited by its sample size and the lack of diversity among participants.

These results indicated that evinacumab was effective at reducing LDL-c among patients with homozygous or heterozygous familial hypercholesterolemia as well as among patients with undetermined hypercholesterolemia.

Disclosure: Multiple authors declared affiliations with industry. Please refer to the original article for a full list of disclosures.


Rosenson RS, Burgess LJ, Ebenbichler CF, et al. Evinacumab in patients with refractory hypercholesterolemia. N Engl J Med. 2020;383(24):2307-2319. doi:10.1056/NEJMoa2031049