Reduction in lipoprotein-associated apoC-III levels following volanesorsen therapy: phase 2 randomized trial results1

Journal of Lipid Research

卷:57

Yun-Seok Choi¹  Andres Digenio²  Yury I. Miller³  Xiaohong Yang⁴  Veronica J. Alexander⁴  Sang-Rok Lee⁴  Sotirios Tsimikas⁵  Joseph L. Witztum⁶  Qingqing Yang⁶ 

[1] Division of Cardiology, Chonbuk National University Hospital and Chonbuk School of Medicine, Jeonju, Korea;

[2] Division of Cardiology, Department of Internal Medicine, College of Medicine, Catholic University of Korea, Seoul, Korea;

[3] Akcea Therapeutics, Cambridge, MA;

[4] Division of Cardiovascular Medicine, Sulpizio Cardiovascular Center, University of California San Diego, La Jolla, CA;

[5] Division of Endocrinology and Metabolism, University of California San Diego, La Jolla, CA;

[6] Ionis Pharmaceuticals, Carlsbad, CA;

关键词: hypertriglyceridemia;    triglycerides;    remnant lipoproteins;    antisense oligonucleotides;    cardiovascular disease;    familial chylomicronemia syndrome;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown