• Joseph L Witztum, Daniel Gaudet, Steven D Freedman, Veronica J Alexander, Andres Digenio, Karren R Williams, Qingqing Yang, Steven G Hughes, Richard S Geary, Marcello Arca, Stroes Erik S G ESG From the Department of Medicine, University of California San Diego, La Jolla (J.L.W., S.T.), and Ionis Pharmaceuticals, Carlsbad (V.J.A., Q.Y., S.G.H, Jean Bergeron, Handrean Soran, Fernando Civeira, Linda Hemphill, Sotirios Tsimikas, Dirk J Blom, Louis O'Dea, and Eric Bruckert.
• From the Department of Medicine, University of California San Diego, La Jolla (J.L.W., S.T.), and Ionis Pharmaceuticals, Carlsbad (V.J.A., Q.Y., S.G.H., R.S.G., S.T.) - both in California; the Department of Medicine, Université de Montréal and ECOGENE 21, Chicoutimi, QC (D.G.), and the Department of Medicine and Laboratory Medicine, Centre Hospitalier Universitaire de Québec-University Laval, Quebec, QC (J.B.) - both in Canada; the Department of Medicine, Beth Israel Deaconess Medical Center (S.D.F.), and the Department of Medicine, Massachusetts General Hospital (L.H.), Boston, and Akcea Therapeutics, Cambridge (A.D., K.R.W., L.O.) - all in Massachusetts; Dipartimento di Medicina Interna e Specialità Mediche, Sapienza Università di Roma, Rome (M.A.); Academic Medical Center, Department of Vascular Medicine, Amsterdam (E.S.G.S.); the Department of Medicine, Manchester University Hospital NHS Foundation Trust, Manchester, United Kingdom (H.S.); the Department of Internal Medicine, Hospital Universitario Miguel Servet, IIS Aragón, Universidad de Zaragoza, Zaragoza, Spain (F.C.); the Division of Lipidology and Hatter Institute for Cardiovascular Research in Africa, University of Cape Town, Cape Town, South Africa (D.J.B.); and the Department of Endocrinology and Cardiovascular Disease Prevention, Assistance Publique-Hôpitaux de Paris, La Pitié-Salpêtrière Hospital, Institut de Création et d'Animation Numériques, Paris (E.B.).
• N. Engl. J. Med. 2019 Aug 8; 381 (6): 531-542.

BackgroundFamilial chylomicronemia syndrome is a rare genetic disorder that is caused by loss of lipoprotein lipase activity and characterized by chylomicronemia and recurrent episodes of pancreatitis. There are no effective therapies. In an open-label study of three patients with this syndrome, antisense-mediated inhibition of hepatic APOC3 mRNA with volanesorsen led to decreased plasma apolipoprotein C-III and triglyceride levels.MethodsWe conducted a phase 3, double-blind, randomized 52-week trial to evaluate the safety and effectiveness of volanesorsen in 66 patients with familial chylomicronemia syndrome. Patients were randomly assigned, in a 1:1 ratio, to receive volanesorsen or placebo. The primary end point was the percentage change in fasting triglyceride levels from baseline to 3 months.ResultsPatients receiving volanesorsen had a decrease in mean plasma apolipoprotein C-III levels from baseline of 25.7 mg per deciliter, corresponding to an 84% decrease at 3 months, whereas patients receiving placebo had an increase in mean plasma apolipoprotein C-III levels from baseline of 1.9 mg per deciliter, corresponding to a 6.1% increase (P<0.001). Patients receiving volanesorsen had a 77% decrease in mean triglyceride levels, corresponding to a mean decrease of 1712 mg per deciliter (19.3 mmol per liter) (95% confidence interval [CI], 1330 to 2094 mg per deciliter [15.0 to 23.6 mmol per liter]), whereas patients receiving placebo had an 18% increase in mean triglyceride levels, corresponding to an increase of 92.0 mg per deciliter (1.0 mmol per liter) (95% CI, -301.0 to 486 mg per deciliter [-3.4 to 5.5 mmol per liter]) (P<0.001). At 3 months, 77% of the patients in the volanesorsen group, as compared with 10% of patients in the placebo group, had triglyceride levels of less than 750 mg per deciliter (8.5 mmol per liter). A total of 20 of 33 patients who received volanesorsen had injection-site reactions, whereas none of the patients who received placebo had such reactions. No patients in the placebo group had platelet counts below 100,000 per microliter, whereas 15 of 33 patients in the volanesorsen group had such levels, including 2 who had levels below 25,000 per microliter. No patient had platelet counts below 50,000 per microliter after enhanced platelet-monitoring began.ConclusionsVolanesorsen lowered triglyceride levels to less than 750 mg per deciliter in 77% of patients with familial chylomicronemia syndrome. Thrombocytopenia and injection-site reactions were common adverse events. (Funded by Ionis Pharmaceuticals and Akcea Therapeutics; APPROACH Clinical Trials.gov number, NCT02211209.).Copyright © 2019 Massachusetts Medical Society.

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