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

Abstract

ApoC-III is a 79 amino acid glycoprotein synthesized principally in the liver and associated with apoB-containing lipoproteins and HDL ( 1 ). apoC-III plays a key role in determining serum triglyceride levels and is a potent inhibitor of both the LPL-dependent and -independent pathways of triglyceride-rich lipoprotein (TRL) clearance. Thus, apoC-III inhibits the apoC-II-mediated activation of LPL and also inhibits hepatic lipase that plays an important role in the conversion of dense VLDL to IDL. Furthermore, apoC-III also inhibits TRL clearance by inhibiting receptor-mediated uptake of TRL by the liver ( 2 ).Recent work has shown that the CVD risk of circulating plasma apoC-III is not uniform, but rather dependent on its association with specifi c lipoproteins ( 3-5 ). This suggests that the effect of both LDL and HDL on CVD risk is context-dependent on the presence or absence of apoC-III. However, current methods to detect apoC-III on LDL or HDL utilize labor-intensive immunoprecipitation of apoC-III and/or ultracentrifugation methods that can only be 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 apoCIIIapoAI 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 fi brate (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, apo-CIII-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 fi rst 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.

Anti-sense oligonucleotide therapies for the treatment of hyperlipidaemia

“…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 resulted in a 82 ± 12% in apoB-apoC3, 81 ± 16% in Lp(a)-apoC3, and 81 ± 14% reduction in apoA1-apoC3 concentrations at day 92. Strong correlations were seen with these results and with total apoC3, chylomicron-apoC3, and VLDL-apoC3 [52].…”

β-Catenin mRNA Silencing and MEK Inhibition Display Synergistic Efficacy in Preclinical Tumor Models

“…Specific target engagement in patients has been demonstrated for oligonucleotide therapeutics in cardiovascular diseases (54), viral infection (55), rare genetic diseases (56) and cancer (57). For the latter, safe and efficient tumor-selective drug delivery technology remains a key limitation.…”

Emerging strategies of targeting lipoprotein lipase for metabolic and cardiovascular diseases

“…A dose-dependent decrease in the plasma APOC3 levels was observed in volanesorsen-treated patients with an accompanying decrease in plasma TG levels ranging from 31.3% to 70.9% over the placebo group. Using a novel high-throughput chemiluminescent ELISA, authors reported a decrease in APOC3 associated with specific lipoproteins [135]. The therapy was generally well tolerated with no effects on renal or hepatic functions.…”