Novel Monoclonal Antibody Halves LDL Cholesterol Levels

Evinacumab reduced LDL cholesterol by 50% over placebo in high-risk patients with severe hypercholesterolemia whose condition was resistant to standard treatments, according to findings reported at the virtual scientific sessions of the American Heart Association and published simultaneously in the New England Journal of Medicine.

In this exclusive MedPage Today video, principal investigator Robert Rosenson, MD, of the Icahn School of Medicine at Mount Sinai in New York City, discusses the importance of his team's study.

Following is a transcript of his remarks:

I had the opportunity to lead an international trial that investigated the effects of evinacumab, a human monoclonal antibody directed against angiopoietin-like protein 3, in patients with refractory hypercholesterolemia.

Who were these individuals? These were individuals who had elevated LDL cholesterol levels on maximum-targeted statin plus or minus ezetimibe and a PCSK9 inhibitor. All study participants received a PCSK9 inhibitor; thus we are dealing with individuals who have increased risk despite maximal tolerated cholesterol-lowering therapy. About 3 in 4 of the individuals had heterozygous familial hypercholesterolemia diagnosed genetically or fulfilling the Dutch Lipid Clinic Network criteria.

In this study, individuals were randomized to evinacumab 2 to 1 versus placebo. The trial consisted of a subcutaneous arm and an intravenous arm. The subcutaneous arm administered evinacumab every week at different doses, 300 and 450 mg, or evinacumab 300 mg every 2 weeks, and of course there was placebo in the double-blind, placebo-controlled treatment arm.

The other part of the study included once-monthly infusions of evinacumab at two different doses that were adjusted based on body weight versus placebo. In this double-blind treatment period, evinacumab was more effective than placebo in lowering LDL cholesterol. It reduced it by 50% from baseline.

In addition to the reduction in LDL cholesterol, there were reductions in other erythrogenic lipoproteins including lipoprotein A, non-HDL cholesterol, apolipoprotein B, and triglycerides.

The therapy was very well tolerated. There was a minor allergic reaction in one of the treatment groups that resolved after an antihistamine was given. Other than that, the treatment was well tolerated by the study participants.

Why is this study important? Individuals who have familial hypercholesterolemia have a high lifetime risk of atherosclerotic cardiovascular events, most notably coronary heart disease events. The LDL cholesterol level is elevated because most often there is a defect in the LDL receptor, the inability to clear the LDL from the blood circulation because one of the two receptors doesn't work well.

The variability in the LDL cholesterol levels depends on how severe the mutation is for that LDL receptor, worse than people with no mutations, and some mutations have a greater impairment in clearing LDL than others.

We use evidence-based therapies, statins plus or minus ezetimibe or PCSK9 inhibitor, but sometimes these therapies don't effectively lower LDL cholesterol to the levels that have been shown to decrease the risk of cardiovascular event in individuals with atherosclerotic cardiovascular disease. Thus, we needed another option.

Angiopoietin-like 3 protein lowers LDL cholesterol in an LDL receptor independent mechanism. Recent data shows that through its effects on endothelial lipase, angiopoietin-like 3 protein inhibition with evinacumab remodels the VLDL particle and results in a decrease in production of the VLDL particle, which means less of the VLDL gets converted to the LDL particle.

This is an LDL receptor independent mechanism and therefore we are not having the limitations of upregulating a defective LDL receptor, which is present in one of the two individuals.

The results that we present at AHA, that are accepted for simultaneous publication in the New England Journal of Medicine, are consistent with the results that we published earlier this year in patients with homozygous familial hypercholesterolemia.

In that study, evinacumab given once monthly intravenously lowered LDL cholesterol by 49%, so the 50% reduction that we're seeing in patients with refractory hypercholesterolemia, most often heterozygous familial hypercholesterolemia, is in line with the results reported in the patients with homozygous familial hypercholesterolemia.

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