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

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,...

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Published in:Journal of lipid research 2016-04, Vol.57 (4), p.706-713
Main Authors: Yang, Xiaohong, Lee, Sang-Rok, Choi, Yun-Seok, Alexander, Veronica J, Digenio, Andres, Yang, Qingqing, Miller, Yury I, Witztum, Joseph L, Tsimikas, Sotirios
Format: Article
Language:English
Subjects:
Apolipoprotein C-III - blood
Apolipoprotein C-III - genetics
Apolipoprotein C-III - metabolism
Cardiovascular Diseases - blood
Cardiovascular Diseases - genetics
Cardiovascular Diseases - therapy
Female
Humans
Male
Middle Aged
Oligonucleotides, Antisense - genetics
Oligonucleotides, Antisense - therapeutic use
Patient-Oriented and Epidemiological Research
RNA, Messenger - genetics
Triglycerides - blood
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Summary: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.
ISSN:0022-2275
1539-7262
DOI:10.1194/jlr.M066399