Regeneron’s Antibody Therapy Reduces LDL Cholesterol in Hypercholesterolemia Patients

On November 15th, a Regeneron sponsored team from the Icahn School of Medicine published the results of a Phase 2 study (NCT03175367) that evaluated the efficacy of Evinacumab in patients with primary hypercholesterolemia with most having heterozygous familial hypercholesterolemia (HeFH). The study published in The New England Journal of Medicine showed that the drug significantly reduced the LDL cholesterol level by greater than 50% when administered at the maximum dose.

Evinacumab

Evinacumab is a human monoclonal antibody that brings dangerously high cholesterol to normal levels when combined with maximally-tolerated lipid-lowering therapies. The drug works by inhibiting angiopoietin-like protein 3 (ANGPLT3) and lowers LDL cholesterol independently of the LDL receptor pathway.

ANGPLT3 is an inhibitor of both lipoprotein lipase (LPL) and endothelial lipase (EL), which increases the levels of plasma triglycerides, LDL, and HDL cholesterol in mice and humans. It inhibits endothelial lipase hydrolysis of HDL-phospholipid (PL), thereby increasing HDL-PL levels. PL-rich HDL particles have high cholesterol efflux abilities when circulating through the bloodstream. People who are missing or have low levels of ANGPTL3 are more likely to have low lifelong levels of LDL cholesterol and rarely suffer from atherosclerotic cardiovascular disease.

The Phase 2, placebo-controlled study comprised of 272 people who randomly received either evinacumab or placebo. Results showed that after 16 weeks, patients who received a subcutaneous dose of 450 mg evinacumab weekly had reduced LDL cholesterol by 56% compared to placebo. On the other hand, those who received a monthly intravenous injection of 15 mg evinacumab per kilogram of body weight had reduced LDL cholesterol by 50.5%.

Competitor Technology

The more typical therapy for hypercholesterolemia patients is called “triple therapy.” This consists of a high-intensity statin (a drug that blocks the enzyme that creates cholesterol), a Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, and ezetimibe, a drug that limits the absorption of cholesterol from the intestine.

PCSK9 is an enzyme that binds to low-density lipoprotein receptors (LDL receptors), which stop LDL from being removed from the blood, leading to an increase in blood levels of LDL. Using an inhibitor on this enzyme makes removing LDL cholesterol from the blood much easier and works well with cholesterol not being absorbed from the intestine due to the ezetimibe.

Future Predictions

As compared to daily dose medications like statins, which have negative side effects, Evinacumab is administered as a monthly dose. Additionally, it is devoid of long-term side effects of statins, like high blood sugar and liver damage.

The regulatory authorities of both the US and EU are evaluating Evinacumab as a supplement to other lipid-lowering therapies in patients with homozygous familial hypercholesterolemia.

“There’s an unmet need for agents that address refractory hypercholesterolemia through a pathway that’s independent of the LDL receptor,” explains Dr. Rosenson. “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.”

Assuming that this drug makes it through the approval process, the consumer and the American market as a whole can look forward to lightening the toll to quality of life taken by high cholesterol and the diseases that it causes. High cholesterol is responsible for hypertension, stroke, peripheral and coronary heart disease, and these afflictions take 786,000 lives annually and a substantial drain of time and expense for Americans to keep under control. With 93 million US adults having high cholesterol, the success of Evinacumab is something that many can hope for.

By Eduardo Longoria

Related Article: FDA Approval of Cholesterol Lowering Drug, NEXLETOL, A Value-Add to Existing Treatments

References

1. https://www.nejm.org/doi/full/10.1056/NEJMoa2031049

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Author

Eduardo Longoria