NLA 2025: Data on ApoC3 Inhibitors Shows Promise Across a Spectrum of Hypertriglyceridemic Disorders

In the field of lipidology, emerging therapies targeting apolipoprotein C-III (ApoC3) are altering the management of hypertriglyceridemia and associated cardiovascular risks, according to Daniel Gaudet, MD, PhD, a professor of medicine at the Université de Montréal in Canada. At the 2025 National Lipid Association (NLA) Scientific Sessions in Miami, Florida, Gaudet explained that ApoC3, a small glycoprotein with a pivotal role in triglyceride (TG) metabolism, was recognized 50 years ago as a potent inhibitor of lipoprotein lipase (LPL) and a contributor to remnant lipoprotein accumulation. However, results from recent clinical trials have reinvigorated investigation into ApoC3 inhibition for patients with severe hypertriglyceridemia (sHTG) and rare disorders such as familial chylomicronemia syndrome (FCS).¹

An illustration of triglyceride molecules in fat cells. Image Credit: © Kraiwit - stock.adobe.com

ApoC3, Gaudet explained, is a 79-amino acid glycoprotein encoded by the APOC3 gene, known for its potent inhibitory effects on LPL and hepatic lipase. By interfering with the lipolytic breakdown of TG-rich lipoproteins—including chylomicrons and very-low-density lipoproteins—ApoC3 plays a central role in the persistence of high circulating TG levels. Beyond its enzymatic interactions, ApoC3 also impedes the hepatic clearance of lipoprotein remnants, a mechanism that has been increasingly implicated in cardiovascular disease (CVD) risk. As Gaudet noted, several studies have positioned ApoC3 not just as a contributor to hypertriglyceridemia but as an independent risk factor for atherosclerotic CVD (ASCVD).¹

“The clinical interest in inhibiting ApoC3 in preventing CVD or pancreatitis stems primarily from the identification quite recently—published 17 years ago—of naturally occurring loss-of-function variants in the APOC3 gene, the carriers [of which] were presenting favorable lipid profiles,” Gaudet said during the NLA presentation. “A lot of carriers were not exhibiting features of CVD over many years. I'm not sure what created the loss of function that has been described, but large cohorts are available now showing the same pattern of negative association with CVD.”¹

According to Gaudet, carriers of these loss-of-function variants consistently exhibit lower TG levels and a reduced incidence of ASCVD. This genetic evidence, Gaudet explained, provides a strong rationale for pharmacologically inhibiting ApoC3 to mimic this protective phenotype.¹

A compelling aspect of ApoC3 inhibition is its efficacy in sHTG populations, including patients with FCS, where LPL activity is virtually absent. Gaudet emphasized that the ability of ApoC3 inhibitors to lower TG levels in these patients highlights the existence of LPL-independent pathways.¹

In the current therapeutic landscape, the most advanced ApoC3 inhibitors are GalNAc conjugated antisense oligonucleotides (ASOs) and small interfering RNA (siRNA) agents, according to Gaudet. Specifically, 2 leading candidates are olezarsen (Tryngolza; Ionis Pharmaceuticals), a GalNAc-conjugated ASO, and plozasiran (ARO-APOC3; Arrowhead Pharmaceuticals), a GalNAc-conjugated siRNA. Both agents are designed to specifically target ApoC3 mRNA in hepatocytes, utilizing GalNAc conjugation to enhance delivery via the asialoglycoprotein receptor. This liver-targeting strategy ensures more efficient uptake, reduced systemic exposure, and prolonged duration of action compared to earlier-generation agents such as volanesorsen (Waylivra; Ionis Pharmaceuticals), a non-GalNAc-conjugated ASO that was hampered by frequent injections and thrombocytopenia risk.¹

Olezarsen and plozasiran have demonstrated consistent efficacy across a broad range of TG disorders. Clinical trials have reported reductions in ApoC3 levels by approximately 70%, with corresponding TG reductions ranging from 40% to 80%. Gaudet highlighted data from key trials, including the BALANCE trial (NCT02795676), which assessed olezarsen in patients with FCS; the SHASTA-2 trial (NCT04720534), which assessed plozasiran in sHTG; and the MUIR trial (NCT04998201), which assessed plozasiran in mixed dyslipidemia.^1-4 Notably, in the BALANCE trial, olezarsen achieved a 92% reduction in ApoC3 levels and a 74% reduction in TG in patients with FCS. Plozasiran showed similarly robust results, with TG reductions of up to 81% in the SHASTA-2 trial and 74% in the MUIR study.¹

These agents are also progressing in terms of regulatory approval. On December 19, 2024, the FDA approved olezarsen for the treatment of adults with FCS, marking a significant milestone in addressing this rare disease.^1,5 On January 17, 2025, the new drug application for plozasiran to treat persistent chylomicronemia was accepted by the FDA, with regulatory approval anticipated later in 2025.^1,6 Phase 3 trials for both agents are ongoing, with expanded indications being explored across a spectrum of hypertriglyceridemic disorders, from moderate elevations to severe chylomicronemia.¹

Gaudet also addressed the adverse effect profiles of ApoC3 inhibitors, noting that while thrombocytopenia was a concern with earlier agents such as volanesorsen, it has not been observed with GalNAc-conjugated therapies. However, an increase in low-density lipoprotein cholesterol (LDL-C) levels has been consistently reported, which is likely attributable to the accelerated hydrolysis of TG-rich lipoproteins, leading to the formation of LDL particles. Gaudet explained that these LDL particles are typically larger, depleted of ApoC3, and potentially less atherogenic. Additionally, mild hyperglycemia has been observed in some trials, particularly in patients with type 2 diabetes, though the underlying mechanisms are still under investigation.¹

The growing body of evidence supporting ApoC3 inhibition marks a significant advancement in the treatment of hypertriglyceridemia and related cardiovascular risks, offering hope to patients with rare and severe lipid disorders who have long faced limited therapeutic options. As olezarsen enters clinical practice and plozasiran nears potential regulatory approval, these innovative therapies are poised to transform the landscape of lipid management.

“The most advanced ApoC3 inhibitors are plozasiran and olezarsen… and their efficacy and tolerability profiles are very, very similar,” Gaudet said. “I would like to dedicate this presentation to all patients affected with severe disorders, and to the health care providers and those pioneers who have made [these therapies] possible.”¹

REFERENCES

1. Gaudet D. APOC3 inhibitors: Innovations in TG-management and cardioprotection. NLA Scientific Sessions; Miami, Florida; May 29-June 1.

2. Study of the Safety and Efficacy of PRX-102 Compared to Agalsidase Beta on Renal Function (BALANCE). Clinicaltrials.gov. Updated September 13, 2023. Accessed May 30, 2025. https://clinicaltrials.gov/study/NCT02795676

3. Study to Evaluate ARO-APOC3 in Adults With Severe Hypertriglyceridemia (SHASTA-2). Clinicaltrials.gov. Updated April 18, 2024. Accessed May 30, 2025. https://clinicaltrials.gov/study/NCT04720534?term=NCT04720534&rank=1

4. Study of ARO-APOC3 in Adults With Mixed Dyslipidemia (MUIR). Clinicaltrials.gov. Updated April 18, 2024. Accessed May 30, 2025. https://clinicaltrials.gov/study/NCT04998201?term=NCT04998201&rank=1

5. TRYNGOLZA™ (olezarsen) approved in U.S. as first-ever treatment for adults living with familial chylomicronemia syndrome as an adjunct to diet. Ionis Pharmaceuticals. December 19, 2024. Accessed May 30, 2025. https://ir.ionis.com/news-releases/news-release-details/tryngolzatm-olezarsen-approved-us-first-ever-treatment-adults

6. Arrowhead Pharmaceuticals Announces Acceptance of New Drug Application by U.S. FDA of Plozasiran for the Treatment of Familial Chylomicronemia Syndrome. January 17, 2025. Accessed May 30, 2025. https://www.businesswire.com/news/home/20250117349461/en/Arrowhead-Pharmaceuticals-Announces-Acceptance-of-New-Drug-Application-by-U.S.-FDA-of-Plozasiran-for-the-Treatment-of-Familial-Chylomicronemia-Syndrome