ApoCIII inhibitors

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).