Novel monoclonal antibody therapy halves LDL cholesterol in a high-risk patient population

The investigational drug evinacumab reduced low-density lipoprotein (LDL) cholesterol, the so-called “bad” cholesterol, by 50% in patients with severe hypercholesterolemia whose condition is resistant to standard treatments, a phase 2 study by Icahn School of Medicine of Mount Sinai and other global academic sites have found. The results of the Regeneron-sponsored study are presented as “late science” at the American Heart Association’s 2020 scientific sessions on Sunday, November 15 and simultaneously published in The New England Journal of Medicine.

Evinacumab is a fully human monoclonal antibody that works through a different mechanism than existing drugs to bring dangerously high cholesterol to normal levels when combined with maximally tolerated lipid-lowering therapies in people with familial hypercholesterolemia, a common inherited condition that is difficult to treat.

“Our study evaluating the safety and efficacy of evinacumab shows that it can reduce LDL cholesterol in half in patients unable to achieve target guidelines despite maximally tolerated lipid-lowering therapy,” says lead investigator Robert Rosenson, MD, Professor of Medicine (Cardiology) and Director of Cardiometabolic Disorders at the Icahn School of Medicine on Mount Sinai. “Evinacumab is a fully human monoclonal antibody that inhibits angiopoietin protein 3 (ANGPLT3) and lowers LDL cholesterol through an LDL receptor-independent pathway. Genetic studies have shown that people who lack or have low levels of ANGPTL3 are known to have very low levels of ANGPTL3 lifelong LDL cholesterol levels and rarely suffer from atherosclerotic cardiovascular disease. “

In the United States, approximately 7% of adults have been diagnosed with severe hypercholesterolemia, which is defined as untreated LDL cholesterol at levels greater than or equal to 190 mg per deciliter. Familial hypercholesterolemia occurs in 1 in 313 people, but is much more common in patients with early-onset cardiovascular disease, occurring in 1 in 15. The American Heart Association / American Congress of Cardiology 2018 recommends a cholesterol goal LDL less than or equal to 70 mg per deciliter in patients with very high risk of atherosclerotic cardiovascular disease and more aggressive targets have been set by European Society of Cardiology guidelines with recommendations for lowering LDL cholesterol to 55 mg / dL or less. These goals have proved difficult for patients with hypercholesterolemia to achieve through the standard “triple therapy” of a high-intensity statin, a PCSK9 inhibitor and ezetimibe, a drug that limits the absorption of cholesterol from the gut.

“There is an unmet need for agents that address refractory hypercholesterolemia through an LDL receptor-independent pathway,” says Dr. Rosenson. “If approved by the US Food and Drug Administration, evinacumab can potentially fill this clinical gap for patients by reducing severely elevated LDL cholesterol.”

The Phase 2 multicentre, double-blind, placebo-controlled study of evinacumab included 272 patients with primary hypercholesterolaemia, the majority diagnosed with heterozygous familial hypercholesterolaemia (HeFH). HeFH is an inherited form of hypercholesterolemia most often caused by mutations in the LDL receptor gene. The research team found that subcutaneous administration of the agent at 450 mg per week resulted in lowering of LDL cholesterol by 56% and 52.9% at 300 mg per week compared to the placebo group. With monthly intravenous administration of evinacumab at 15 mg / kg, the reduction in LDL cholesterol was 50.5% compared to the placebo group. All patients receiving evinacumab were on background lipid-lowering therapy.

Evinacumab was well tolerated by most patients. One patient treated with subcutaneous evinacumab had difficulty breathing and another had a mild anaphylactic reaction. They both stopped treatment and their symptoms improved with other treatments. Two deaths were reported in the study, but linked to underlying health conditions.

“Our study shows that a subcutaneous or intravenous regimen of evinacumab can have a significant impact on LDL cholesterol,” notes Dr. Rosenson. “If approved for use in this setting, evinacumab could potentially provide cardiologists with an important new adjunct therapy to bring HeFH patients closer or closer to their cholesterol-lowering goal.”

Evinacumab is under regulatory review in the United States and the European Union in addition to other lipid-lowering therapies in patients with homozygous familial hypercholesterolaemia, another form of familial hypercholesterolemia.