ApoCIII inhibitors
ApoCIII is a critical determinant of how efficiently TGs are cleared from the plasma, involving direct inhibition of lipoprotein lipase, as well as indirect mechanisms, such as promoting secretion of TG-rich lipoproteins, provoking proinflammatory responses in vascular cells and impairing lipoprotein lipase-independent hepatic clearance of triglyceride-rich lipoprotein remnants (1). Mendelian randomisation studies have shown that loss-of-function variants in APOCIII were associated with low TG, as well as a reduced risk of coronary artery disease (2).Volanesorsen (Waylivra)
Volanesorsen is an antisense oligonucleotide that inhibits the production of apoCIII. It is currently indicated as an adjunct to diet in adult patients with genetically confirmed familial chylomicronaemia syndrome and at high risk for pancreatitis, in whom response to diet and TG-lowering therapy has been inadequate (3). Clinical trials have shown that volanesorsen reduces TG levels by 70-80% in patients with familial chylomicronaemia syndrome, as well as rates of pancreatitis (4). In another trial in patients with multifactorial chlyomicronaemia, volanesorsen reduced TG levels by ~70% and might reduce acute pancreatitis events in these patients (5).Olezarsen (formerly AKCEA-APOCIII-LRx)
Olezarsen (formerly AKCEA-APOCIII-LRx) is an antisense medicine designed to reduce the production of apoC-III, and is approved in the USA for use in adults with familial chylomicronaemia syndrome (FCS) as an adjunct to diet. The approval is supported by clinical trial data including from the Phase 3 Balance study in patients with genetically identified FCS and fasting TG levels ≥880 mg/dL treated with olezarsen 80 mg or 50 mg.Plozasiran (formerly ARO-APOC3)
Plozasiran is an investigational RNA interference (RNAi) therapeutic that is designed to inhibit the production of apolipoprotein CIII (apoCIII) in the regulation of triglyceride metabolism. In the MUIR, SHASTA-2 and PALISADE trials, it has been shown to reduce triglyceride levels in patients with mixed dyslipidaemia, severe hypertriglyceridaemia and familial chylomicronaemia syndrome respectively. Further studies including SHASTA-3, SHASTA-4, SHASTA-5 and SHASTA-10, and CAPITAN are underway or planned.View key references >
- Taskinen MR, Borén J. Why Is apolipoprotein CIII emerging as a novel therapeutic target to reduce the burden of cardiovascular disease? Curr Atheroscler Rep 2016;18:59. PUBMED https://pubmed.ncbi.nlm.nih.gov/27613744/
- Jørgensen AB, Frikke-Schmidt R, Nordestgaard BG, Tybjærg-Hansen A. Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. N Engl J Med 2014;37132-41. PUBMED https://pubmed.ncbi.nlm.nih.gov/24941082/
- Volanesorsen (Waylivra). Summary of Product Characteristics. https://www.ema.europa.eu/en/documents/product-information/waylivra-epar-product-information_en.pdf
- Witztum JL, Gaudet D, Freedman SD, et al. Volanesorsen and triglyceride levels in familial chylomicronemia syndrome. N Engl J Med 2019;381:531-42. PUBMED https://pubmed.ncbi.nlm.nih.gov/31390500/
- Gouni-Berthold I, Alexander VJ, Yang Q, et al. Efficacy and safety of volanesorsen in patients with multifactorial chylomicronaemia (COMPASS): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Diabetes Endocrinol;9:264-75. PUBMED https://pubmed.ncbi.nlm.nih.gov/33798466/
