Introduction and Objective: We assessed the efficacy of olezarsen, an antisense oligonucleotide targeting APOC3, in pts with severe hypertriglyceridemia (sHTG) and DM.Methods: The phase 3 RCTs CORE-TIMI 72a (N=617) and CORE2-TIMI 72b (N=446) randomized pts with sHTG (TG ≥500mg/dL) 1:1:1 to SC olezarsen 50mg, 80mg, or placebo Q4W for 12 mths. The primary endpoint was placebo-adjusted % change in TGs at 6 mths. Secondary endpoints included acute pancreatitis (AP).Results: Of 1,063 pts, 673 (63%) had DM (median HbA1c 7.3% [IQR 6.6-8.2]; DM duration 9 [4-14] yrs; 25% on GLP-1RAs and 37% on insulin). Baseline TGs were similar in pts with DM (median 784 [IQR 589-1,224] mg/dL) vs w/o DM (807 [606-1,269] mg/dL; P=0.43), but those with DM were more likely to have had prior AP (21% vs. 14%; p=0.005). During the trial, pts with DM were at a 3.6-fold higher risk of AP compared with pts w/o DM (IR 3.76 vs 1.04/100PY; IRR 3.6 [1.1-12.0], P=0.034). Compared with placebo, the 50 mg & 80 mg doses of olezarsen reduced TGs by 57.4% (95% CI 48.6-66.2) and 64.8% (56.0-73.6) in pts with DM, respectively, and by 57.0% (45.7-68.3) and 65.1% (53.9-76.4) in pts w/o DM (Fig A). Olezarsen treatment (pooled) reduced the risk of AP compared with placebo, with absolute reductions of 6.91/100PY in DM and 2.86/100PY in no-DM (Fig B).Conclusion: Olezarsen lowered TGs by 57-65% and risk of AP in pts with sHTG & DM, a population at higher baseline risk of AP.
Y. Kang: None. B. Bergmark: Research Support; Current; Amgen, Ionis, Pfizer, Philips, Inari, AstraZeneca, Abbott Vascular. Consultant; Current; Shockwave, Teleflex, Abbott Vascular, Abiomed, Bain Life Science, Morgan Stanley, SpectraWAVE, Bolt, Boston Scientific. V.J. Alexander: Employee; Current; Ionis Pharmaceuticals. T.A. Prohaska: Employee; Current; Ionis Pharmaceuticals. Stock/Shareholder; Current; Ionis Pharmaceuticals. X. Ran: Other – Institutional research grant to the TIMI Study Group at Brigham and Women’s Hospital to conduct the CORE trials; Current; Ionis Pharmaceuticals. Other – I am a member of the TIMI Study Group which has received institutional research grant support through Brigham and Women’s Hospital from Abbott, Abiomed, Inc., Amgen, Anthos Therapeutics, ARCA Biopharma, Inc., AstraZeneca, Boehringer Ingelheim, Cleerly, Inc., Daiichi-Sankyo, Janssen Research and Development, LLC, MedImmune, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Roche,; Current; other company. S. Murphy: Other – Institutional research grant to the TIMI Study Group at Brigham and Women’s Hospital to conduct the CORE trials; Current; Ionis Pharmaceuticals. Other – I am a member of the TIMI Study Group which has received institutional research grant support through Brigham and Women’s Hospital from Abbott, Abiomed, Inc., Amgen, Anthos Therapeutics, ARCA Biopharma, Inc., AstraZeneca, Boehringer Ingelheim, Cleerly, Inc., Daiichi-Sankyo, Janssen Research and Development, LLC, MedImmune, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Roche,; Current; Many – see Other field. E.L. Goodrich: Other – Institutional research grant to the TIMI Study Group at Brigham and Women’s Hospital; Current; Ionis Pharmaceuticals. F. Moura: None. A. Zimerman: Advisory Panel; Ended; Novartis Pharmaceuticals Corporation. Speaker’s Bureau; Ended; Novartis Pharmaceuticals Corporation. E. Waldman: Employee; Current; Ionis Pharmaceuticals. J. Weinland: Employee; Current; Ionis Pharmaceuticals. Stock/Shareholder; Current; Ionis Pharmaceuticals. S. Zhang: None. S. Xia: Employee; Current; Ionis Pharmaceuticals. D. Li: None. S. Tsimikas: Employee; Current; Ionis Pharmaceuticals. R.P. Giugliano: Research Support; Current; Amgen Inc., Daiichi Sankyo, Ionis Pharmaceuticals, Novartis AG. Other – Honoraria for Academic Lectures / CME programs; Current; Amgen Inc., Daiichi Sankyo. Other – Honoraria for Academic Lectures / CME programs; Ended; Dr. Reddy’s Laboratories Ltd. Other – Honoraria for Academic Lectures / CME programs; Current; Medical Education Resources. Other – Honoraria for Academic Lectures / CME programs; Ended; SUMMEET. Consultant; Current; Daiichi Sankyo, Inventiva Pharma. M.S. Sabatine: Other – Institutional research grant to the TIMI Study Group at Brigham and Women’s Hospital; Consulting; Current; Amgen Inc., AstraZeneca, Boehringer Ingelheim International GmbH. Research Support; Current; Inno Medicine, Ionis Pharmaceuticals, Marea. Other – Institutional research grant to the TIMI Study Group at Brigham and Women’s Hospital; Consulting; Current; Merck & Co., Inc. Research Support; Current; Novartis AG, Pfizer Inc. Consultant; Current; General Medicines. N. Marston: Research Support; Current; Ionis Pharmaceuticals. Advisory Panel; Current; Ionis Pharmaceuticals. Research Support; Current; Amgen Inc. Advisory Panel; Current; Amgen Inc. Research Support; Current; Marea Therapeutics. Advisory Panel; Current; Arrowhead Pharmaceuticals, Inc. Advisory Panel; Ended; New Amsterdam. Advisory Panel; Current; Radence, Arboretum.
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