Olezarsen, Acute Pancreatitis, and Familial Chylomicronemia Syndrome.

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  • Additional Information
    • Corporate Authors:
      Balance Investigators
    • Source:
      Publisher: Massachusetts Medical Society Country of Publication: United States NLM ID: 0255562 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1533-4406 (Electronic) Linking ISSN: 00284793 NLM ISO Abbreviation: N Engl J Med Subsets: MEDLINE
    • Publication Information:
      Original Publication: Boston, Massachusetts Medical Society.
    • Subject Terms:
      Pancreatitis*/drug therapy ; Apolipoprotein C-III*/blood ; Triglycerides*/blood ; Hyperlipoproteinemia Type I*/drug therapy ; Hyperlipoproteinemia Type I*/blood ; Hyperlipoproteinemia Type I*/complications; Humans ; Male ; Female ; Double-Blind Method ; Middle Aged ; Adult ; Acute Disease ; Oligonucleotides/therapeutic use ; Oligonucleotides/adverse effects ; Aged ; Hypertriglyceridemia/drug therapy ; Hypertriglyceridemia/blood ; Young Adult
    • Abstract:
      Background: Familial 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.
      Methods: In 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.
      Results: A 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.
      Conclusions: In 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.)
    • Comments:
      Comment in: Nat Rev Cardiol. 2024 Jun;21(6):353. (PMID: 38654089)
    • Contributed Indexing:
      Investigator: J Bergeron; S Bernard; D Gaudet; P Moulin; R Valero; B Verges; I Reiber; O Hussein; A Alberti; M Arca; M Averna; G Iannuzzo; E Sjoerd; G Stroes; K Retterstol; T Curdia Goncalves; J Sequeira Duarte; K Raslova; A Blanco; JL Diaz Diaz; O Muniz; D Zambon; M Eriksson; S Romeo; D Nair; H Soran; A Wierzbicki; Z Ahmad; A Bajaj; C Ballantyne; A Brown; S Baum; H Ginsberg; I Goldberg; K Hilty; M Linton; P Moriarty; A Morise; E Oral; P Rosenblit; E Stock; J Trippi; RC Becker; PB Duell; JP Dwyer; WC Maddrey; LJ Wei; M Bruno; P Ruszniewski; G Webster
    • Molecular Sequence:
      ClinicalTrials.gov NCT04568434
    • Publication Date:
      Date Created: 20240408 Date Completed: 20240515 Latest Revision: 20240522
    • Publication Date:
      20240523
    • Accession Number:
      10.1056/NEJMoa2400201
    • Accession Number:
      38587247