N-Acetyl Galactosamine-Conjugated Antisense Drug to APOC3 Mrna, Triglycerides and Atherogenic Lipoprotein Levels
European Heart Journal (2019) 40, 2785–2796 CLINICAL RESEARCH doi:10.1093/eurheartj/ehz209 Lipids N-acetyl galactosamine-conjugated antisense drug to APOC3 mRNA, triglycerides and atherogenic lipoprotein levels Veronica J. Alexander1, Shuting Xia1, Eunju Hurh2, Steven G. Hughes1, Louis O’Dea2, Richard S. Geary1, Joseph L. Witztum3, and Sotirios Tsimikas1,4* 1Ionis Pharmaceuticals, Inc., 2855 Gazelle Ct, Carlsbad, CA 92010, USA; 2Akcea Therapeutics, 22 Boston Wharf Road, 9th Floor, Boston, MA 02210, USA; 3Division of Endocrinology and Metabolism, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0682, USA; and 4Division of Cardiovascular Medicine, Sulpizio Cardiovascular Center, Vascular Medicine Program, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0682, USA Received 15 January 2019; revised 8 March 2019; editorial decision 25 March 2019; accepted 4 April 2019; online publish-ahead-of-print 24 April 2019 See page 2797 for the editorial comment on this article (doi: 10.1093/eurheartj/ehz321) Aims Elevated apolipoprotein C-III (apoC-III) levels are associated with hypertriglyceridaemia and coronary heart disease. AKCEA-APOCIII-LRx is an N-acetyl galactosamine-conjugated antisense oligonucleotide targeted to the liver that selectively inhibits apoC-III protein synthesis. ................................................................................................................................................................................................... Methods The safety, tolerability, and efficacy of AKCEA-APOCIII-LRx was assessed in a double-blind, placebo-controlled, and results dose-escalation Phase 1/2a study in healthy volunteers (ages 18–65) with triglyceride levels >_90 or >_200 mg/dL. Single-dose cohorts were treated with 10, 30, 60, 90, and 120 mg subcutaneously (sc) and multiple-dose cohorts were treated with 15 and 30 mg weekly sc for 6 weeks or 60 mg every 4 weeks sc for 3 months.
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