• StroesErik S GESGFrom the Department of Vascular Medicine, Amsterdam University Medical Center, Amsterdam, (E.S.G.S.); Ionis Pharmaceuticals, Carlsbad (V.J.A., E.K.-P., T.A.P., S.X., S.T.), and the Divisions of Endocrinology and Metabolism (J.L.W.) and Ca, Veronica J Alexander, Ewa Karwatowska-Prokopczuk, Robert A Hegele, Marcello Arca, Christie M Ballantyne, Handrean Soran, Thomas A Prohaska, Shuting Xia, Henry N Ginsberg, Joseph L Witztum, Sotirios Tsimikas, and Balance Investigators.
• From the Department of Vascular Medicine, Amsterdam University Medical Center, Amsterdam, (E.S.G.S.); Ionis Pharmaceuticals, Carlsbad (V.J.A., E.K.-P., T.A.P., S.X., S.T.), and the Divisions of Endocrinology and Metabolism (J.L.W.) and Cardiovascular Medicine (S.T.), Department of Medicine, University of California, San Diego, La Jolla - both in California; the Department of Medicine and Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada (R.A.H.); the Department of Translational and Precision Medicine, Center for Rare Disorders of Lipid Metabolism, Sapienza University of Rome, Rome (M.A.); Baylor College of Medicine and the Texas Heart Institute, Houston (C.M.B.); the National Institute for Health Research and Wellcome Trust Clinical Research Facility, Manchester University Hospital NHS Foundation Trust, Manchester, United Kingdom (H.S.); and the Department of Medicine, Columbia University Vagelos College of Physicians and Surgeons, New York (H.N.G.).
• N. Engl. J. Med. 2024 May 16; 390 (19): 178117921781-1792.

BackgroundFamilial chylomicronemia syndrome is a genetic disorder associated with severe hypertriglyceridemia and severe acute pancreatitis. Olezarsen reduces the plasma triglyceride level by reducing hepatic synthesis of apolipoprotein C-III.MethodsIn a phase 3, double-blind, placebo-controlled trial, we randomly assigned patients with genetically identified familial chylomicronemia syndrome to receive olezarsen at a dose of 80 mg or 50 mg or placebo subcutaneously every 4 weeks for 49 weeks. There were two primary end points: the difference between the 80-mg olezarsen group and the placebo group in the percent change in the fasting triglyceride level from baseline to 6 months, and (to be assessed if the first was significant) the difference between the 50-mg olezarsen group and the placebo group. Secondary end points included the mean percent change from baseline in the apolipoprotein C-III level and an independently adjudicated episode of acute pancreatitis.ResultsA total of 66 patients underwent randomization; 22 were assigned to the 80-mg olezarsen group, 21 to the 50-mg olezarsen group, and 23 to the placebo group. At baseline, the mean (±SD) triglyceride level among the patients was 2630±1315 mg per deciliter, and 71% had a history of acute pancreatitis within the previous 10 years. Triglyceride levels at 6 months were significantly reduced with the 80-mg dose of olezarsen as compared with placebo (-43.5 percentage points; 95% confidence interval [CI], -69.1 to -17.9; P<0.001) but not with the 50-mg dose (-22.4 percentage points; 95% CI, -47.2 to 2.5; P = 0.08). The difference in the mean percent change in the apolipoprotein C-III level from baseline to 6 months in the 80-mg group as compared with the placebo group was -73.7 percentage points (95% CI, -94.6 to -52.8) and between the 50-mg group as compared with the placebo group was -65.5 percentage points (95% CI, -82.6 to -48.3). By 53 weeks, 11 episodes of acute pancreatitis had occurred in the placebo group, and 1 episode had occurred in each olezarsen group (rate ratio [pooled olezarsen groups vs. placebo], 0.12; 95% CI, 0.02 to 0.66). Adverse events of moderate severity that were considered by a trial investigator at the site to be related to the trial drug or placebo occurred in 4 patients in the 80-mg olezarsen group.ConclusionsIn patients with familial chylomicronemia syndrome, olezarsen may represent a new therapy to reduce plasma triglyceride levels. (Funded by Ionis Pharmaceuticals; Balance ClinicalTrials.gov number, NCT04568434.).Copyright © 2024 Massachusetts Medical Society.

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