By Michael H. Crawford, MD, Editor

SYNOPSIS: In patients with familial hypercholesterolemia who are not at target LDL cholesterol levels on maximum-tolerated doses of statins and PCSK9 inhibitors, evinacumab, which inhibits angiopoietin-like 3, reduces LDL by more than 50% at the highest doses with few side effects requiring drug discontinuation vs. placebo.

SOURCE: Rosenson RS, Burgess LJ, Ebenbichler CF, et al. Evinacumab in patients with refractory hypercholesterolemia. N Engl J Med 2020; Nov 15. doi: 10.1056/NEJMoa2031049. [Online ahead of print].

Angiopoietin-like 3 (ANGPTL3) regulates lipid metabolism by inhibiting lipoprotein lipase and endothelial lipase. Patients without functioning ANGPTL3 record low levels of LDL cholesterol, triglycerides, and HDL cholesterol. Also, they are at a reduced risk of coronary artery disease. Evinacumab is a human monoclonal antibody against ANGPTL3 and lowers LDL cholesterol by means not involving the LDL receptor.

Rosenson et al assessed the efficacy and safety of subcutaneous and intravenous evinacumab vs. placebo in patients with refractory hypercholesterolemia despite therapy with maximum-tolerated doses of statins and a PCSK9 inhibitors, with or without ezetimibe. The authors conducted the study in 85 sites across 20 countries. They enrolled 272 patients with either heterozygous familial hypercholesterolemia or non-heterozygous hypercholesterolemia and clinically diagnosed cardiovascular disease. Refractory hyperlipidemia was defined as an LDL cholesterol level > 70 mg/dL with atherosclerotic disease or greater than 100 mg/dL without atherosclerotic disease.

Patients were randomized to receive subcutaneous treatment or intravenous treatment at various doses. Intravenous evinacumab was administered every four weeks and subcutaneous every one or two weeks. The primary endpoint was percent change from baseline in the LDL cholesterol level at 16 weeks. The various drug dose and route of administration groups included 30 to 40 patients each. Six patients did not receive treatment, so the final intention to treat population was 266. The heterozygous variant was present in 72% of patients. The differences in LDL cholesterol between baseline and week 16 in the subcutaneous evinacumab at 450 mg weekly, 300 mg weekly, and 300 mg every two weeks groups were -56%, -53%, and -39%, respectively (P = 0.001 for all). The differences in the intravenous groups at 15 mg/kg and 5 mg/kg were -51% (P = 0.001) and -24%. All atherogenic lipoprotein levels decreased with evinacumab, except lipoprotein (a).

The incidence of side effects with subcutaneous evinacumab that occurred in at least 5% of the subjects included injection site erythema in 6% vs. 3% on placebo and myalgia in 5% vs. zero on placebo. Adverse events with intravenous evinacumab that occurred in more than 5% of the subjects included abdominal pain in 6% vs. zero with placebo, dizziness in 7% vs. zero with placebo, and nausea 7% vs. zero with placebo. The authors concluded using evinacumab significantly reduced LDL cholesterol levels by more than 50% at maximal doses in patients with refractory hypercholesterolemia with few side effects requiring drug discontinuation vs. placebo.

COMMENTARY

In many patients with familial hypercholesterolemia, LDL levels remain above guideline targets despite statins and PCSK9 inhibitors. Some produce adverse effects, especially to statins, that also limit the dose tolerated. Thus, there is residual need for other agents to reduce LDL cholesterol. This is the case especially in those with atherosclerotic disease or at high risk for it when one considers the 2016 ESC and ACC/AHA guidelines recommend an LDL < 70 mg/dL for such patients and the 2019 ESC guidelines recommend < 55 mg/dL.

Evinacumab in the Rosenson et al study is impressive at reducing LDL in these high-risk patients with familial hypercholesterolemia and others at high risk of atherosclerotic vascular disease. With either subcutaneous or intravenous administration, the LDL levels had decreased significantly by two weeks and continued for 16 weeks. Side effects were common in the treatment groups and the placebo groups, but serious adverse effects requiring drug discontinuation above that seen with placebo were few and only observed at the highest doses. Evinacumab reduces triglycerides, which are atherogenic, whereas PCSK9 inhibitors do not. Evinacumab also decreases apolipoprotein B, which is associated with reduced cardiovascular disease risk. In addition, evinacumab reduces HDL cholesterol. However, in those with naturally occurring low ANGPTL3 function, there is no increase in cardiovascular disease risk.

There were limitations to the Rosenson et al study. The size of each dose and administration group were small, and the study was not ethnically diverse. Also, only one-third of patients were on ezetimibe. In addition, it was a short-term study, and the authors did not provide outcome data. Still, evinacumab looks promising, and cardiologists need an additional class of drugs to treat patients with very high LDL cholesterol levels. I look forward to longer-term studies with outcome data.