• Gerald F Watts, Robert S Rosenson, Robert A Hegele, Ira J Goldberg, Antonio Gallo, Ann Mertens, Alexis Baass, Rong Zhou, Ma'an Muhsin, Jennifer Hellawell, Nicholas J Leeper, Daniel Gaudet, and PALISADE Study Group.
• From the School of Medicine, University of Western Australia, and the Department of Cardiology, Royal Perth Hospital - both in Perth, Australia (G.F.W.); the Metabolism and Lipids Program, Mount Sinai Fuster Heart Hospital, Icahn School of Medicine at Mount Sinai (R.S.R.), and New York University (NYU) Grossman School of Medicine, NYU Langone Health (I.J.G) - both in New York; Robarts Research Institute, London, ON (R.A.H.), and the Department of Medicine, McGill University, and the Genetic Dyslipidemia Clinic, Montreal Clinical Research Institute (A.B.) and Université de Montréal and ECOGENE-21 (D.G.), Montreal - all in Canada; Sorbonne University, INSERM UMR1166, Lipidology and Cardiovascular Prevention Unit, Department of Nutrition, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Paris (A.G.); the Department of Endocrinology, University Hospitals Leuven-KU Leuven, Leuven, Belgium (A.M.); and Arrowhead Pharmaceuticals, Pasadena (R.Z., M.M., J.H.), and Stanford University, Palo Alto (N.J.L.) - both in California.
• N. Engl. J. Med. 2024 Sep 2.

BackgroundPersistent chylomicronemia is a genetic recessive disorder that is classically caused by familial chylomicronemia syndrome (FCS), but it also has multifactorial causes. The disorder is associated with the risk of recurrent acute pancreatitis. Plozasiran is a small interfering RNA that reduces hepatic production of apolipoprotein C-III and circulating triglycerides.MethodsIn a phase 3 trial, we randomly assigned 75 patients with persistent chylomicronemia (with or without a genetic diagnosis) to receive subcutaneous plozasiran (25 mg or 50 mg) or placebo every 3 months for 12 months. The primary end point was the median percent change from baseline in the fasting triglyceride level at 10 months. Key secondary end points were the percent change in the fasting triglyceride level from baseline to the mean of values at 10 months and 12 months, changes in the fasting apolipoprotein C-III level from baseline to 10 months and 12 months, and the incidence of acute pancreatitis.ResultsAt baseline, the median triglyceride level was 2044 mg per deciliter. At 10 months, the median change from baseline in the fasting triglyceride level (the primary end point) was -80% in the 25-mg plozasiran group, -78% in the 50-mg plozasiran group, and -17% in the placebo group (P<0.001). The key secondary end points showed better results in the plozasiran groups than in the placebo group, including the incidence of acute pancreatitis (odds ratio, 0.17; 95% confidence interval, 0.03 to 0.94; P = 0.03). The risk of adverse events was similar across groups; the most common adverse events were abdominal pain, nasopharyngitis, headache, and nausea. Severe and serious adverse events were less common with plozasiran than with placebo. Hyperglycemia with plozasiran occurred in some patients with prediabetes or diabetes at baseline.ConclusionsPatients with persistent chylomicronemia who received plozasiran had significantly lower triglyceride levels and a lower incidence of pancreatitis than those who received placebo. (Funded by Arrowhead Pharmaceuticals; PALISADE ClinicalTrials.gov number, NCT05089084.).Copyright © 2024 Massachusetts Medical Society.

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