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The investigational drug evinacumab lowered low-density lipoprotein (LDL) cholesterol, the so-called “bad” cholesterol, by 50 percent in patients with severe hypercholesterolemia whose condition is resistant to standard treatments, a phase 2 study of the Mount Sinai Icahn School of Medicine and other global academic sites.
The results of the Regeneron-sponsored study are presented as “breaking science” at the American Heart Association 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 lipid-lowering therapies that are maximally tolerated in people with familial hypercholesterolemia, a common inherited condition that is It is difficult to treat.
Our study evaluating the safety and efficacy of evinacumab shows that it can reduce LDL cholesterol by half in patients who cannot achieve target guidelines despite maximally tolerated lipid-lowering therapy. “
Robert Rosenson, MD, Principal Investigator, Professor of Medicine (Cardiology) and Director of Cardiometabolic Disorders, Icahn School of Medicine, Mount Sinai Hospital
“Evinacumab is a fully human monoclonal antibody that inhibits angiopoietin-like 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 have very low levels of LDL cholesterol throughout life and rarely suffer from atherosclerotic cardiovascular disease. “
In the United States, approximately 7 percent of adults have been diagnosed with severe hypercholesterolemia, which is defined as having 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 2018 American Heart Association / American Congress of Cardiology recommends a goal of LDL cholesterol of less than or equal to 70 mg per deciliter in patients at very high risk of atherosclerotic cardiovascular disease, and the European Society of Cardiology guideline has set more aggressive targets with recommendations to lower LDL cholesterol to 55 mg / dL or less.
These goals have proven elusive for hypercholesterolemic patients using standard “triple therapy” of a high-intensity statin, a PCSK9 inhibitor, and ezetimibe, a drug that limits cholesterol absorption from the gut.
“There is an unmet need for agents that address refractory hypercholesterolemia through a pathway that is independent of the LDL receptor,” explains Dr. Rosenson. “If approved by the US Food and Drug Administration, Evinacumab could fill that clinical gap for patients by lowering very high LDL cholesterol.”
The phase 2 multicenter, double-blind, placebo-controlled study of evinacumab included 272 patients with primary hypercholesterolaemia, including the majority with a diagnosis of heterozygous familial hypercholesterolaemia (HFH).
HeFH is a hereditary 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 weekly resulted in a 56 percent reduction in LDL cholesterol and 52.9 percent at 300 mg weekly compared to the placebo group.
With the monthly intravenous administration of evinacumab at 15 mg / kg, the reduction of LDL cholesterol was 50.5 percent compared to the placebo group. All patients who received evinacumab were on background lipid-lowering therapy.
Evinacumab was well tolerated by most of the patients. One patient treated with subcutaneous evinacumab had difficulty breathing and another had a mild anaphylactic reaction. They both stopped taking the medication and their symptoms improved with other treatments. Two deaths were reported in the trial, but they were linked to underlying health conditions.
“Our study demonstrates 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 provide cardiologists with an important new add-on therapy to bring HeFH patients closer to their cholesterol-lowering 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.
Source:
Mount Sinai Hospital / Mount Sinai School of Medicine
