ApoCII 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 ANGPTL3 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).
AKCEA-APOCIII-LRx
AKCEA-APOCIII-LRx is an investigational antisense medicine designed to reduce the production of apoC-III. It is in Phase 3 development for patients with familial chylomicronaemia syndrome, with evaluation also planned in other hypertriglyceridaemia disorders.
In a Phase 1/2a study, AKCEA-APOCIII-LRx treatment of healthy volunteers (ages 18–65) with triglyceride levels ≥ 90 or ≥ 200 mg/dL resulted in a broad improvement in the atherogenic lipid profile with a favourable safety and tolerability profile (6).
View References >
1. 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/
2. 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/
3. Volanesorsen (Waylivra). Summary of Product Characteristics. https://www.ema.europa.eu/en/documents/product-information/waylivra-epar-product-information_en.pdf
4. 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/
5. 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/
6. Alexander VJ, Xia S, Huth E et al. N-acetyl galactosamine-conjugated antisense drug to APOC3 mRNA, triglycerides and atherogenic lipoprotein levels. European Heart Journal 2019; 40: 2785-2796 https://pubmed.ncbi.nlm.nih.gov/31329855/
2. 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/
3. Volanesorsen (Waylivra). Summary of Product Characteristics. https://www.ema.europa.eu/en/documents/product-information/waylivra-epar-product-information_en.pdf
4. 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/
5. 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/
6. Alexander VJ, Xia S, Huth E et al. N-acetyl galactosamine-conjugated antisense drug to APOC3 mRNA, triglycerides and atherogenic lipoprotein levels. European Heart Journal 2019; 40: 2785-2796 https://pubmed.ncbi.nlm.nih.gov/31329855/