Novel agents

In recent years, there has been rapid progress in the development of novel agents that target key proteins involved in the regulation of TG metabolism. Clinical trial data have shown that these agents reduce TG levels and, in some studies, the risk of pancreatitis. Such trials have supported the approval of the first of these novel agents for use in clinical practice.

ApoC3 inhibitors (eg. volanesorsen, olezarsen, and plozasiran) target apoC3, which determines how efficiently TGs are cleared from the plasma, through direct inhibition of lipoprotein lipase (LpL), as well as indirect mechanisms, such as promoting secretion of TG-rich lipoproteins, provoking proinflammatory responses in vascular cells and impairing LpL-independent hepatic clearance of TRL remnants.¹ Mendelian randomisation studies have shown that loss-of-function variants in the APOC3 gene were associated with low TG, as well as a reduced risk of coronary artery disease.²

• In clinical trials, volanesorsen reduced TG levels by 77% in patients with familial chylomicronaemia syndrome (FCS),³ and by approximately 70% in patients with multifactorial chylomicronaemia.⁴ Volanesorsen is approved in Europe as an adjunct to diet in adult patients with genetically confirmed FCS and at high risk for pancreatitis, in whom response to diet and TG lowering therapy has been inadequate
• In the Phase 3 Balance trial, olezarsen 80 mg significantly reduced TG levels at 6 months by 43.5% (95% confidence interval [CI], −69.1 to −17.9; p<0.001) compared with placebo in patients with FCS.⁵ In 2024, these results supported the approval of olezarsen as an adjunct to diet in patients with FCS in the USA, with the same indication approved in Europe in 2025
• Pooled data from the Phase 3 CORE-TIMI 72a and CORE2-TIMI 72b studies of olezarsen in patients with severe hypertriglyceridaemia (sHTG) showed a placebo-adjusted mean reduction in fasting TG levels of up to 72% at 6 months (p<0.001), remaining stable at 12 months, and an 85% reduction in acute pancreatitis events at 12 months (p<0.001)⁶
• In the ESSENCE–TIMI 73b trial of olezarsen in patients with moderate HTG (fasting TG 150 mg/dL to <500 mg/dL, median 238.5 mg/dL) and elevated CV risk, the placebo-adjusted mean change in TG level was up to 61% with olezarsen at 6 months (p<0.001)⁷
• In the Phase 3 PALISADE trial in patients with persistent chylomicronaemia, plozasiran 25 mg reduced fasting TG by 80% at month 10, compared with a 17% reduction with placebo (p<0.001). There was also a reduction in the incidence of acute pancreatitis (odds ratio, 0.17; 95% confidence interval, 0.03 to 0.94; p= 0.03).⁸ Plozasiran received US approval as an adjunct to diet to in adults with FCS in 2025
• In the Phase 2 SHASTA-2 trial in patients with sHTG, there was a placebo-adjusted mean reduction in TG with plozasiran 50 mg of 57% and 47% at 24 and 48 weeks, respectively (p<0.0001)⁹
• In the Phase 2b MUIR study in patients with mixed dyslipidaemia including elevated TG, TG was reduced by 64% with plozasiran 50 mg compared to 2% with placebo (p<0.0001) at week 24.¹⁰At week 48, TG was reduced by 50% with plozasiran 50 mg compared to a 2% increase with placebo (p<0.0001).

ANGPTL3 inhibitors (eg. evinacumab, zodasiran and solbinsiran) target ANGPTL3 (produced in the liver) which plays a key role in the regulation of lipid metabolism by inhibiting LpL and endothelial lipase in adipose and muscle tissue. Mendelian randomisation studies have shown that loss-of-function variants in ANGPTL3 are associated with low levels of LDL-C, HDL-C and TG, as well as a reduced risk of coronary artery disease.^11-12

• In clinical trials in patients with sHTG, homozygous familial hypercholesterolaemia (HoFH) and refractory hypercholesterolaemia, evinacumab at highest doses reduced TG levels by more than 50%.¹³ Evinacumab is approved in the USA and Europe for the treatment of adults and children with HoFH
• In the ARCHES-2 trial of zodasiran in patients with mixed dyslipidaemia, zodasiran 50 mg-200 mg reduced TG levels at week 24 by 51%-63% compared with placebo (p<0.001 for all comparisons).¹⁴
• In the PROLONG-ANG trial of solbinsiran in patients with mixed dyslipidaemia, solbinsiran 100 mg-800 mg reduced TG levels at day 180 by 36.3%-52.5% compared to placebo (p<0.0001 for all comparisons).¹⁵ In patients with hepatic steatosis (fat fraction ≥8% at baseline), there were dose-dependent reductions in hepatic fat of 10.3%-26.9% at week 24 compared to placebo

ANGPTL4 inhibitors (eg. MAR001) target ANGPTL4 which, like apoC3 and ANGPTL3, inhibits LpL.¹⁶ Loss-of-function mutations in ANGPTL4 are associated with lower plasma TG and higher plasma HDL-C levels, and a reduced risk of coronary artery disease and diabetes.¹⁷

• In a Phase1/2b study of MAR001 in participants with metabolic dysfunction, there were placebo-adjusted reductions in mean TG at week 12 of up to 53%.¹⁸

Gene editing agents (eg.VERVE-201), are designed to permanently inactivate ANGPTL3 in the liver via a precise A-to-G DNA base pair edit and thereby lower LDL-C and TG concentrations. Preclinical research with VERVE-201 supports its ANGPTL3-targeting effects.

For further information about these and other trials of TG-lowering agents view the Trials section.

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.
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.
3. Witztum JL, Gaudet D, Freedman SD, et al. Volanesorsen and triglyceride levels in familial chylomicronemia syndrome. N Engl J Med 2019;381:531-42.
4. 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.
5. Stroes ESG, Alexander VJ, Karwatowska-Prokopczuk E et al. Olezarsen, acute pancreatitis, and Familial Chylomicronemia Syndrome. N England J Medicine 2024; 390:1781-1792
6. Marston NA, Bergmark BA, Alexander VJ et al. Olezarsen for managing severe hypertriglyceridemia and pancreatitis risk. N Engl J Med. 2025 Nov 8. Epub ahead of print
7. Bergmark BA, Marston NA, Prohaska TA et al; Essence–TIMI 73b Investigators. Targeting APOC3 with Olezarsen in Moderate Hypertriglyceridemia. N Engl J Med. 2025 Oct 2;393(13):1279-1291
8. Watts GF, Rosenson RS, Hegele RA, et al; PALISADE Study Group. Plozasiran for Managing Persistent Chylomicronemia and Pancreatitis Risk. N Engl J Med. 2025 Jan 9;392(2):127-137.
9. Gaudet D, Pall D, Watts GF et al. Plozasiran (ARO-APOC3) for Severe Hypertriglyceridemia: The SHASTA-2 Randomized Clinical Trial. JAMA Cardiol. 2024 Jul 1;9(7):620-630
10. Ballantyne CM, Vasas S, Azizad M et al. Plozasiran, an RNA Interference Agent Targeting APOC3, for Mixed Hyperlipidemia. N Engl J Med. 2024 12;391(10):899-912.
11. Kersten S. New insights into angiopoietin-like proteins in lipid metabolism and cardiovascular disease risk. Curr Opin Lipidol 2019;30:205-11.
12. Dewey FE, Gusarova V, Dunbar RL et al. Genetic and pharmacologic inactivation of ANGPTL3 and cardiovascular disease. N Engl J Med 2017; 377: 211-21. 
13. Rosenson RS, Rader DJ, Ali S et al. Evinacumab Reduces Triglyceride-Rich Lipoproteins in Patients with Hyperlipidemia: A Post-Hoc Analysis of Three Randomized Clinical Trials. Cardiovasc Drugs Ther. 2024 Mar 6.
14. Rosenson RS, Gaudet D, Hegele RA et al. Zodasiran, an RNAi Therapeutic Targeting ANGPTL3, for Mixed Hyperlipidemia. N Engl J Med. 2024  Sep 12;391(10):913-925. 
15. Ray KK, Oru E, Rosenson RS et al. Durability and efficacy of solbinsiran, a GalNAc-conjugated siRNA targeting ANGPTL3, in adults with mixed dyslipidaemia (PROLONG-ANG3): a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet. 2025 Mar 28:S0140-6736(25)00507-0.  
16. Kersten S. Role and mechanism of the action of angiopoietin-like protein ANGPTL4 in plasma lipid metabolism. J Lipid Res. 2021;62:100150.
17. Landfors F, Henneman P, Chorell E et al. Drug-target Mendelian randomization analysis supports lowering plasma ANGPTL3, ANGPTL4, and APOC3 levels as strategies for reducing cardiovascular disease risk. Eur Heart J Open. 2024 Apr 30;4(3):oeae035.
18. Cummings BB, Joing MP, Bouchard PR et al. Safety and efficacy of a novel ANGPTL4 inhibitory antibody for lipid lowering: results from phase 1 and phase 1b/2a clinical studies. Lancet. 2025 May 31;405(10493):1923-1934