Hypertriglyceridaemia - Emerging treatments

Treatments to reduce apolipoprotein C-III (apo C-III)

Apo C-III is a protein that circulates with triglyceride (TG)-rich lipoproteins, affects lipoprotein metabolism, and is associated with increased atherosclerotic cardiovascular disease (ASCVD) risk.[67] Volanesorsen, an antisense oligonucleotide designed to inhibit the formation of apo C-III, impairs translation of apo C-III mRNA.[68][69][70] The European Medicines Agency (EMA) has approved volanesorsen as an adjunct to diet in adults with genetically confirmed familial chylomicronaemia syndrome (FCS) who are at high risk for pancreatitis, and in whom a response to diet and triglyceride-lowering therapy has been inadequate. Volanesorsen causes thrombocytopenia, and it is contraindicated in patients with chronic or unexplained thrombocytopenia. The US Food and Drug Administration (FDA) did not approve volanesorsen because of the risk of thrombocytopenia. Olezarsen, a ligand conjugated antisense oligonucleotide targeting apo C-III, has been shown to reduce TG by >50% and acute pancreatitis risk by >85% in patients with FCS and also to reduce TG levels in patients with mild-to-moderate HTG who are considered to be at risk for ASCVD.[71][72] Olezarsen is approved by the FDA as an adjunct to diet to reduce TG levels in adults with FCS. However, this indication is for a rare and severely affected genetic subgroup of patients and is not for standard severe HTG or mild-to-moderate HTG. Olezarsen is not approved in Europe as yet. Therefore, due to its limited indication and lack of availability, olezarsen is not routinely used in clinical practice yet. Plozasiran, an investigational small interfering RNA (siRNA) drug, has been shown to reduce TG levels and incidence of acute pancreatitis in patients with severe HTG and with mixed hyperlipidaemia, and a clinical trial of this agent in patients with FCS is pending.[73][74][75][76] Plozasiran is being reviewed by the FDA for approval. Olezarsen and plozasiran are not meant to be given during episodes of acute pancreatitis, but instead for prevention of future HTG-related episodes.

Treatments to reduce angiopoietin-like protein 3 (ANGPTL3)

ANGPTL3 is another genetically validated target for HTG to reduce cholesterol, triglycerides, and ASCVD risk.[77][78] The monoclonal antibody evinacumab and the investigational antisense therapies vupanorsen and zodasiran reduce ANGPTL3, and have shown reductions of triglyceride levels of 50% to 80%.[68][79] However, development of both vupanorsen and zodasiran has been terminated by their respective manufacturers due to concerns over potential adverse effects and a lack of efficacy.

Novel krill-derived omega-3 phospholipid/free fatty acid

Omega-3-phospholipid/free fatty acid (omega-3-PL/FFA) is a new investigational agent derived from krill oil. Pooled data from the TRILOGY 1 and 2 phase 3 randomised controlled trials showed that in patients with severe hypertriglyceridaemia (fasting TG levels from 500 to 1500 mg/dL), omega-3-PL/FFA reduced blood triglyceride levels compared with placebo at 12 weeks (26.0% compared with 15.1%), with reductions persisting at 26 weeks, and that omega-3-PL/FFA was safe and well tolerated.[80]