title: Reduction in lipoprotein-associated apoC-III levels following volanesorsen therapy: phase 2 randomized trial results.
abstract: Elevated apoC-III levels predict increased cardiovascular risk when present on LDL and HDL particles. We developed novel high-throughput chemiluminescent ELISAs that capture apoB, lipoprotein (a) [Lp(a)], and apoA-I in plasma and then detect apoC-III on these individual lipoproteins as apoCIII-apoB, apoCIII-Lp(a), and apoCIII-apoAI complexes, respectively. We assessed the effects on these complexes of placebo or 100-300 mg volanesorsen, a generation 2.0+ antisense drug that targets apoC3 mRNA in patients with hypertriglyceridemia, including familial chylomicronemia syndrome (n = 3), volanesorsen monotherapy (n = 51), and as add-on to fibrate (n = 26), treated for 85 days and followed for 176 days. Compared with placebo, volanesorsen was associated with an 82.3 ± 11.7%, 81.3 ± 15.7%, and 80.8 ± 13.6% reduction in apoCIII-apoB, apoCIII-Lp(a), and apoCIII-apoA-I, respectively (300 mg dose;P< 0.001 for all), at day 92. Strong correlations in all assay measures were noted with total plasma apoC-III, chylomicron-apoC-III, and VLDL-apoC-III. In conclusion, novel high-throughput ELISAs were developed to detect lipoprotein-associated apoC-III, including for the first time on Lp(a). Volanesorsen uniformly lowers apoC-III on apoB-100, Lp(a), and apoA-I lipoproteins, and may be a potent agent to reduce triglycerides and cardiovascular risk mediated by apoC-III.
authors: Division of Cardiovascular Medicine, Sulpizio Cardiovascular Center, University of California San Diego, La Jolla, CA.
authors: Xiaohong
authors: X
authors: Yang
authors: Division of Cardiovascular Medicine, Sulpizio Cardiovascular Center, University of California San Diego, La Jolla, CA Division of Cardiology, Chonbuk National University Hospital and Chonbuk School of Medicine, Jeonju, Korea.
authors: Sang-Rok
authors: SR
authors: Lee
authors: Division of Cardiovascular Medicine, Sulpizio Cardiovascular Center, University of California San Diego, La Jolla, CA Division of Cardiology, Department of Internal Medicine, College of Medicine, Catholic University of Korea, Seoul, Korea.
authors: Yun-Seok
authors: YS
authors: Choi
authors: Ionis Pharmaceuticals, Carlsbad, CA.
authors: Veronica J
authors: VJ
authors: Alexander
authors: Akcea Therapeutics, Cambridge, MA.
authors: Andres
authors: A
authors: Digenio
authors: Ionis Pharmaceuticals, Carlsbad, CA.
authors: Qingqing
authors: Q
authors: Yang
authors: Division of Endocrinology and Metabolism, University of California San Diego, La Jolla, CA.
authors: Yury I
authors: YI
authors: Miller
authors: Division of Endocrinology and Metabolism, University of California San Diego, La Jolla, CA.
authors: Joseph L
authors: JL
authors: Witztum
authors: Division of Cardiovascular Medicine, Sulpizio Cardiovascular Center, University of California San Diego, La Jolla, CA Ionis Pharmaceuticals, Carlsbad, CA stsimikas@ucsd.edu.
authors: Sotirios
authors: S
authors: Tsimikas
mesh_terms: D053305:Apolipoprotein C-III / Q000097:blood* / Q000235:genetics* / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000097:blood / Q000235:genetics / Q000628:therapy; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D016376:Oligonucleotides, Antisense / Q000235:genetics* / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics; D014280:Triglycerides / Q000097:blood
chemical_list: D053305:Apolipoprotein C-III; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D014280:Triglycerides
keywords: antisense oligonucleotides; apolipoprotein C-III; cardiovascular disease; familial chylomicronemia syndrome; hypertriglyceridemia; remnant lipoproteins; triglycerides