A clinical trial has shown that in people with an inherited disorder called familial hypercholesterolemia, a monoclonal antibody decreases the levels of low-density lipoprotein (LDL) cholesterol by 50 percent.
The risk of developing atherosclerosis (narrowed arteries) and cardiovascular disease is increased in individuals with elevated levels of low-density lipoprotein (LDL) or ‘bad’ cholesterol in their blood.
Serious hypercholesterolemia is characterized by doctors as uncontrolled levels of LDL cholesterol of at least 190 milligrams per deciliter (mg/dl) of blood.
In the U.S., cardiologists suggest that people at very high risk of cardiovascular disease due to atherosclerosis strive for a blood level of around 70 mg/dl of LDL cholesterol.
Changes in lifestyles can help reduce LDL, but to achieve this goal, people typically need to take cholesterol-lowering drugs. Moreover such genetic variations may make it more difficult for certain individuals to achieve this goal.
Worldwide, there is an inherited disorder called heterozygous familial hypercholesterolemia in around 1 in 250 adults. Typically, this occurs from mutations in a receptor gene that eliminates LDL from the bloodstream.
Doctors typically recommend a typical “triple therapy” for hypercholesterolemia with three types of cholesterol-lowering drugs:
- 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.
A new medication called evinacumab, acting on a different target, could soon be available for individuals whose LDL cholesterol level remains too high after taking the maximum tolerable dose of this drug combination.
A clinical trial published in The New England Journal of Medicine indicates that evinacumab could further reduce LDL levels by about 50 percent in these individuals.
This will be good news for individuals with LDL receptor gene mutations who don’t respond very well to PCSK9 inhibitors.
Robert Rosenson, MD, Director of Cardiometabolic Disorders at the Icahn School of Medicine at Mount Sinai in New York, N.Y., explains: “There is an unmet need for agents that address refractory hypercholesterolemia through a pathway that is independent of the LDL receptor.”
“When they are authorised by the U.S. Evinacumab, administered by the Food and Drug Administration, can potentially fill the patient clinical gap by reducing severely elevated LDL cholesterol, he adds.
Breaking lipids down
The monoclonal antibody that targets a protein called angiopoietin-like 3 (ANGPTL3) is evinacumab. ANGPTL3 usually inhibits lipid-breaking enzymes, including LDL, high-density lipoprotein (HDL), and triglycerides.
There are abnormally low levels of these lipids in the blood in people with a defective version of the gene that makes ANGPTL3. As a consequence, they have a 41 percent lower risk of developing coronary artery disease than the general population.
Drug developers had hoped to replicate these beneficial effects in people with extremely high levels of cholesterol by disabling ANGPTL3 with an antibody.
The researchers randomly allocated 272 individuals to receive either evinacumab, via intravenous or subcutaneous administration at different doses, or placebo treatments in this phase II clinical trial.
Most of the participants had familial hypercholesterolemia that was heterozygous.
After 16 weeks, in those who received a subcutaneous dose of 450 mg of evinacumab weekly, LDL cholesterol had decreased by an average of 56 percent compared with placebo.
For those who received a monthly intravenous injection of 15 mg of evinacumab per kilogram of body weight, there was a 50.5% decrease in LDL cholesterol relative to placebo.
The authors note that subcutaneous administration is preferred by certain individuals because they can do it themselves at home, eliminating 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.”
The authors admit that there were some limitations to their study. The numbers were relatively small in each arm of the study, for instance, and treatment lasted just 16 weeks.
Moreover the ethnic diversity of participants was not as wide as the researchers had hoped, so the findings do not apply to all individuals in the general population.
There was trouble breathing in one of the persons treated with subcutaneous evinacumab, and another had a moderate anaphylactic reaction.
The research was funded by the pharmaceutical company Regeneron, a manufacturer of evinacumab.