Antibody therapy halves ‘bad’ cholesterol levels

A clinical trial has found that a monoclonal antibody reduces low-density lipoprotein (LDL) cholesterol levels by 50% in people with an inherited condition called familial hypercholesterolemia.

Individuals with high levels of low-density lipoprotein (LDL) or “bad” cholesterol in their blood are at increased risk of developing atherosclerosis (narrowed arteries) and cardiovascular disease.

Doctors define severe hypercholesterolemia as untreated LDL cholesterol levels of at least 190 milligrams per deciliter (mg/dl) of blood.

Cardiologists in the U.S. recommend that individuals who are at very high risk of cardiovascular disease due atherosclerosis aim for an LDL cholesterol level of around 70 mg/dl of blood.

Lifestyle changes can help reduce LDL, but people usually need to take cholesterol-lowering drugs to reach this goal. In addition, certain genetic differences can make achieving this objective more difficult for some people.

Worldwide, approximately 1 in 250 adults have an inherited condition called heterozygous familial hypercholesterolemia. This usually results from mutations in a gene for a receptor that removes LDL from the bloodstream.

Doctors usually prescribe a standard “triple therapy” of three types of cholesterol-lowering drugs for hypercholesterolemia:

• A high dose of a statin, which reduces the amount of cholesterol the body produces.
• A PCSK9 inhibitor, which boosts the number of LDL receptors in the liver.
• Ezetimibe, which limits the absorption of cholesterol from the intestine.

For individuals whose LDL cholesterol level remains too high despite taking the maximum tolerable dose of this drug combination, a new drug called evinacumab that acts on a different target may soon be available.

A clinical trial published in The New England Journal of Medicine suggests that evinacumab could further reduce LDL levels in these individuals by around 50%.

This would be good news for people with mutations in the gene for the LDL receptor who don’t respond particularly well to PCSK9 inhibitors.

“There’s an unmet need for agents that address refractory hypercholesterolemia through a pathway that’s independent of the LDL receptor,” explains principal investigator Robert Rosenson, MD, Director of Cardiometabolic Disorders at the Icahn School of Medicine at Mount Sinai in New York, N.Y.

“If approved by the U.S. Food and Drug Administration, evinacumab may potentially fill that clinical gap for patients by reducing severely elevated LDL cholesterol,” he adds.

Breaking down lipids

Evinacumab is a monoclonal antibody that targets a protein called angiopoietin-like 3 (ANGPTL3). Normally, ANGPTL3 inhibits enzymes that break down lipids, including LDL, high-density lipoprotein (HDL), and triglycerides.

People with a faulty version of the gene that makes ANGPTL3 have abnormally low levels of these lipids in their blood. As a result, their chance of developing coronary artery disease is 41% lower than the general population.

By disabling ANGPTL3 with an antibody, drug developers hoped to recreate these beneficial effects in people with very high cholesterol levels.

In this phase II clinical trial, the researchers randomly assigned 272 people to receive either evinacumab — through intravenous or subcutaneous administration at various doses — or placebo treatments.

Most of the participants had heterozygous familial hypercholesterolemia.

After 16 weeks, LDL cholesterol had fallen by an average of 56% compared with placebo in those who received a subcutaneous dose of 450 mg of evinacumab weekly.

Among those who received a monthly intravenous injection of 15 mg evinacumab per kilogram of body weight, LDL cholesterol fell by 50.5% compared with the placebo group.

The authors note that some people prefer subcutaneous administration because they can do it themselves at home, avoiding the need to take time off work to visit a clinic.

Commenting on the findings, Dr. Rosenson concludes:

“Our study demonstrates that a regimen of either subcutaneous or intravenous evinacumab can have a significant impact on LDL cholesterol […] If approved for use in this setting, evinacumab could potentially arm cardiologists with a major new add-on therapy to bring patients with [heterozygous familial hypercholesterolemia] to or closer to their cholesterol-lowering goal.”

Racial diversity

The authors concede that their study had some limitations. For example, the numbers in each arm of the study were relatively small, and treatment lasted only 16 weeks.

In addition, the racial diversity of participants was not as broad as the researchers had hoped, so the results may not apply to all people in the wider population.

One of the people treated with subcutaneous evinacumab had difficulty breathing, and another had a mild anaphylactic reaction.

The pharmaceutical company Regeneron, which makes evinacumab, sponsored the study.

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