ApoC-III (apoC-III) is an apolipoprotein mainly carried by triglyceride-rich lipoproteins, such as chylomicrons and VLDLs. apoC-III prevents hydrolysis of triglycerides by LPL, for example [
51]. In a genetic study, carriers of loss-of-function mutations in
APOC3 had an HR of 0.59 (95% CI 0.41–0.86,
p = 0.007) and 0.64 (95% CI 0.41–0.99,
p = 0.04) for ischaemic vascular disease and ischaemic heart disease respectively [
52]. Volanesorsen, an ASO, was the first apoC-III inhibitor reaching clinical trials, and is given as a subcutaneous formulation twice monthly. Treatment with volanesorsen effectively reduces plasma triglyceride levels in familial chylomicronaemia syndrome and hypertriglyceridaemia by approximately 70–80% [
53]. However, volanesorsen is hampered by the high incidence of adverse effects, including thrombocytopenia and injection-site reactions [
54], precluding use in large patient populations. Recently, a N-acetyl galactosamine-conjugated (GalNAc
3) ASO targeting apoC-III (AKCEA-APOCIII‑L
Rx) was tested in a phase 1/2a trial [
55]. The GalNAc
3 formulation enables specific delivery to the liver, increasing potency while minimising systemic exposure. Indeed, the trial showed potent reductions in triglycerides up to 92%, and administration was without major adverse effects.