• Robert S Rosenson, Lesley J Burgess, Christoph F Ebenbichler, Seth J Baum, StroesErik S GESGFrom the Icahn School of Medicine at Mount Sinai, New York (R.S.R.), and Regeneron Pharmaceuticals, Tarrytown (S.A., N.K., R.H., R.P., Y.D., V.S.) - both in New York; TREAD Research, Cardiology Unit, Department of Internal Medicine and Ty, Shazia Ali, Nagwa Khilla, Robert Hamlin, Robert Pordy, Yuping Dong, Vladimir Son, and Daniel Gaudet.
• From the Icahn School of Medicine at Mount Sinai, New York (R.S.R.), and Regeneron Pharmaceuticals, Tarrytown (S.A., N.K., R.H., R.P., Y.D., V.S.) - both in New York; TREAD Research, Cardiology Unit, Department of Internal Medicine and Tygerberg Hospital, Parow, South Africa (L.J.B.); the Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria (C.F.E.); Excel Medical Clinical Trials, Department of Integrated Medical Sciences, Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton (S.J.B.); the Department of Vascular Medicine, Academic Medical Center, Amsterdam (E.S.G.S.); and the Clinical Lipidology and Rare Lipid Disorders Unit, Department of Medicine, Université de Montréal Community Gene Medicine Center, Montreal, and ECOGENE-21 Clinical and Translational Research Center, Chicoutimi, QC - both in Canada (D.G.).
• N. Engl. J. Med. 2020 Dec 10; 383 (24): 2307-2319.

BackgroundPatients with refractory hypercholesterolemia, who have high low-density lipoprotein (LDL) cholesterol levels despite treatment with lipid-lowering therapies at maximum tolerated doses, have an increased risk of atherosclerosis. In such patients, the efficacy and safety of subcutaneous and intravenous evinacumab, a fully human monoclonal antibody against angiopoietin-like 3, are not known.MethodsIn this double-blind, placebo-controlled, phase 2 trial, we enrolled patients with or without heterozygous familial hypercholesterolemia who had refractory hypercholesterolemia, with a screening LDL cholesterol level of 70 mg per deciliter or higher with atherosclerosis or of 100 mg per deciliter or higher without atherosclerosis. Patients were randomly assigned to receive subcutaneous or intravenous evinacumab or placebo. The primary end point was the percent change from baseline in the LDL cholesterol level at week 16 with evinacumab as compared with placebo.ResultsIn total, 272 patients were randomly assigned to the following groups: subcutaneous evinacumab at a dose of 450 mg weekly (40 patients), 300 mg weekly (43 patients), or 300 mg every 2 weeks (39 patients) or placebo (41 patients); or intravenous evinacumab at a dose of 15 mg per kilogram of body weight every 4 weeks (39 patients) or 5 mg per kilogram every 4 weeks (36 patients) or placebo (34 patients). At week 16, the differences in the least-squares mean change from baseline in the LDL cholesterol level between the groups assigned to receive subcutaneous evinacumab at a dose of 450 mg weekly, 300 mg weekly, and 300 mg every 2 weeks and the placebo group were -56.0, -52.9, and -38.5 percentage points, respectively (P<0.001 for all comparisons). The differences between the groups assigned to receive intravenous evinacumab at a dose of 15 mg per kilogram and 5 mg per kilogram and the placebo group were -50.5 percentage points (P<0.001) and -24.2 percentage points, respectively. The incidence of serious adverse events during the treatment period ranged from 3 to 16% across trial groups.ConclusionsIn patients with refractory hypercholesterolemia, the use of evinacumab significantly reduced the LDL cholesterol level, by more than 50% at the maximum dose. (Funded by Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT03175367.).Copyright © 2020 Massachusetts Medical Society.

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