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

The investigational drug evinacumab reduced low-density lipoprotein (LDL) cholesterol – the so-called “bad” cholesterol – by 50 percent in patients with severe hypercholesterolemia whose condition was resistant to standard treatments, study Phase 2 of Icahn Mount Sinai School of Medicine and other global academic sites were found. The results of the Regeneron-sponsored study are being touted as “late-breaking science” at the American Heart Association’s 2020 Scientific Sessions on Sunday, November 15, and published simultaneously in The New England Journal of Medicine.

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

“Our study evaluating the safety and efficacy of evinacumab shows that it can halve LDL cholesterol in patients unable to meet target recommendations despite lipid-lowering therapy tolerated as much as possible,” says lead researcher Robert Rosenson, MD, professor of medicine (cardiology) and director of cardio-metabolic disorders at Icahn School of Medicine at Mount Sinai. “Evinacumab is a fully human monoclonal antibody that inhibits angiopoietin like protein 3 (ANGPLT3) and lowers LDL cholesterol through a pathway independent of LDL receptors. Genetic studies have shown that people who lack or have low levels of ANGPTL3 are known to have very low levels of ANGPTL3 for life. LDL cholesterol levels and rarely suffer from atherosclerotic cardiovascular disease. “

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

“There is an unmet need for agents that treat refractory hypercholesterolemia through an LDL receptor independent pathway,” explains Dr. Rosenson. “If approved by the United States Food and Drug Administration, evinacumab has the potential to fill this clinical gap for patients, by reducing very high LDL cholesterol.

The multicenter, phase 2, double-blind, placebo-controlled study of evinacumab included 272 patients with primary hypercholesterolemia, the majority of whom were diagnosed with heterozygous familial hypercholesterolemia (HeFH). HeFH is an inherited form of high cholesterol most commonly 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 lower 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 basic lipid-lowering therapy.

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

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

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