• Sotirios Tsimikas, Ewa Karwatowska-Prokopczuk, Ioanna Gouni-Berthold, Jean-Claude Tardif, Seth J Baum, Elizabeth Steinhagen-Thiessen, Michael D Shapiro, Erik S Stroes, Patrick M Moriarty, Børge G Nordestgaard, Shuting Xia, Jonathan Guerriero, Nicholas J Viney, Louis O'Dea, Joseph L Witztum, and AKCEA-APO(a)-LRx Study Investigators.
• From the Divisions of Cardiovascular Medicine (S.T.) and Endocrinology and Metabolism (J.L.W.), University of California, San Diego, La Jolla, and Ionis Pharmaceuticals, Carlsbad (S.T., S.X., N.J.V.) - both in California; Akcea Therapeutics, Boston (E.K.-P., J.G., L.O.); Polyclinic for Endocrinology, Diabetes and Preventive Medicine, University of Cologne, Cologne, Germany (I.G.-B.); Montreal Heart Institute, Université de Montréal, Montreal (J.-C.T.); Excel Medical Clinical Trials, Boca Raton, FL (S.J.B.); the Department of Endocrinology and Metabolism, Charité-Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität Berlin, Berlin Institute of Health, Berlin (E.S.-T.), and the Division of Geriatrics, University Medicine Greifswald, Greifswald (E.S.-T.) - both in Germany; the Center for Preventive Cardiology, Knight Cardiovascular Institute, Oregon Health and Science University, Portland (M.D.S.); the Department of Vascular Medicine, Academic Medical Center, Amsterdam (E.S.S.); the Division of Clinical Pharmacology, Department of Internal Medicine, University of Kansas Medical Center, Kansas City (P.M.M.); and the Department of Clinical Biochemistry and the Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev (B.G.N.), and the Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen (B.G.N.) - all in Denmark.
• N. Engl. J. Med. 2020 Jan 16; 382 (3): 244-255.

BackgroundLipoprotein(a) levels are genetically determined and, when elevated, are a risk factor for cardiovascular disease and aortic stenosis. There are no approved pharmacologic therapies to lower lipoprotein(a) levels.MethodsWe conducted a randomized, double-blind, placebo-controlled, dose-ranging trial involving 286 patients with established cardiovascular disease and screening lipoprotein(a) levels of at least 60 mg per deciliter (150 nmol per liter). Patients received the hepatocyte-directed antisense oligonucleotide AKCEA-APO(a)-LRx, referred to here as APO(a)-LRx (20, 40, or 60 mg every 4 weeks; 20 mg every 2 weeks; or 20 mg every week), or saline placebo subcutaneously for 6 to 12 months. The lipoprotein(a) level was measured with an isoform-independent assay. The primary end point was the percent change in lipoprotein(a) level from baseline to month 6 of exposure (week 25 in the groups that received monthly doses and week 27 in the groups that received more frequent doses).ResultsThe median baseline lipoprotein(a) levels in the six groups ranged from 204.5 to 246.6 nmol per liter. Administration of APO(a)-LRx resulted in dose-dependent decreases in lipoprotein(a) levels, with mean percent decreases of 35% at a dose of 20 mg every 4 weeks, 56% at 40 mg every 4 weeks, 58% at 20 mg every 2 weeks, 72% at 60 mg every 4 weeks, and 80% at 20 mg every week, as compared with 6% with placebo (P values for the comparison with placebo ranged from 0.003 to <0.001). There were no significant differences between any APO(a)-LRx dose and placebo with respect to platelet counts, liver and renal measures, or influenza-like symptoms. The most common adverse events were injection-site reactions.ConclusionsAPO(a)-LRx reduced lipoprotein(a) levels in a dose-dependent manner in patients who had elevated lipoprotein(a) levels and established cardiovascular disease. (Funded by Akcea Therapeutics; ClinicalTrials.gov number, NCT03070782.).Copyright © 2020 Massachusetts Medical Society.

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