Through Previously Unrecognized LPL-Independent Mechanisms

Anti-APOC3 therapies were not initially expected to be effective to treat FCS, a condition characterized by complete or near-complete absence LPL activity. Since apoC-III was traditionally thought to exert its effects through inhibition of LPL-mediated hydrolysis of TRLs [29], targeting apoC-III was presumed to be ineffective in the absence of functional LPL.

However, a clinical study involving three patients with genetically confirmed FCS demonstrated that antisense inhibition of APOC3 with volanesorsen led to marked reductions in plasma triglyceride levels [30]. This unexpected result suggested that apoC-III contributes to hypertriglyceridemia through additional mechanisms beyond LPL inhibition, including impaired hepatic clearance of remnant particles demonstrated subsequently [16] and enhancement of VLDL secretion [31]. This revealed an unanticipated biological pathway and broadened the potential therapeutic scope of apoC-III–targeted interventions.

Targeting ApoC-III for Pancreatitis Reduction

SHTG is widely recognized by clinicians and regulatory agencies as a major risk factor for acute pancreatitis. Although several triglyceride-lowering therapies have been approved for patients with triglyceride levels above 500 mg/dL, no reduction in pancreatitis incidence had been demonstrated until 2024 and 2025 when data with RNA directed therapeutics volanesorsen, olezarsen and plozasiran were published [32,33,34] (Fig. 1).

Fig. 1

Incidence of acute pancreatitis in patients with severe hypertriglyceridemia treated with volanesorsen (A), olezarsen (B), and plozasiran (C). (a) Re-adapted from a meta-analysis of the APPROACH, COMPASS, and BROADEN trials [32] (b). Re-adapted from the Balance trial [33]. (c) Adapted from the PALISADE trial with permission [34]

Volanesorsen is an ASO that targets APOC3 mRNA to suppress apoC-III production. Unlike newer agents, it is not conjugated to GalNAc and is distributed systemically and may suppress apoC-III production in both the liver and intestine, the 2 largest sources of apoC-III production [35]. Volanesorsen was evaluated in an open-label study involving three patients with FCS who lacked functional LPL activity [30]. Subcutaneous administration once weekly for 13 weeks resulted in substantial reductions in apoC-III (71%–90%) and triglyceride levels (56%–86%). These findings demonstrated that apoC-III modulates triglyceride metabolism through an LPL-independent pathway.

The Phase 3 APPROACH trial evaluated the efficacy and safety of subcutaneous volanesorsen (300 mg once weekly) in 66 patients with FCS over 52 weeks [36]. At 3 months, volanesorsen reduced plasma apoC-III and triglyceride levels by 84.2% and 76.5%, respectively, compared to increases of 6.1% and 17.6% in the placebo group. During the study, acute pancreatitis occurred in three placebo-treated patients with four episodes, versus one volanesorsen treated patient with one episode (occurring nine days after the final dose). Notably, no patient with a prior history of acute pancreatitis in the five years preceding volanesorsen treatment experienced a recurrence.

Volanesorsen was further evaluated in the Phase 3 COMPASS trial, which enrolled 113 patients with SHTG or FCS over 26 weeks [37]. Five adjudicated episodes of acute pancreatitis occurred in the placebo group, while no episodes were reported in the volanesorsen group.

In the BROADEN study, volanesorsen was investigated in patients with familial partial lipodystrophy (FPLD), a rare genetic disorder characterized by selective loss of peripheral subcutaneous adipose tissue, resulting in hypertriglyceridemia, insulin resistance, and increased risk of recurrent pancreatitis [38]. In the randomized phase, three adjudicated episodes of acute pancreatitis occurred in the placebo group, while 4 episodes in 1 patient was reported in the volanesorsen group [32].

Data from the three volanesorsen trials were pooled in a meta-analysis of 207 participants, showing that acute pancreatitis occurred in 2 patients (2%) in the volanesorsen group and 9 patients (10%) in the placebo group during the randomized treatment period (odds ratio, 0.18; 95% CI, 0.04–0.82) [32]. Notably, 10 of the 11 patients who developed pancreatitis during the study had experienced prior episodes before randomization. Kaplan–Meier analysis demonstrated a significant difference in pancreatitis-free survival between treatment groups (Fig. 1A). Trial-specific results were directionally consistent with the meta-analysis findings. Importantly, no cases of acute pancreatitis occurred in the volanesorsen group beyond four months after treatment initiation, coinciding with maximal triglyceride reduction, whereas events continued throughout the study period in the placebo group.

In the recent 2025 focused update of the 2019 ESC/EAS guidelines for the management of dyslipidemias, it was recommended that volanesorsen (300 mg/week) should be considered in patients with severe hypertriglyceridemia (>750 mg/dL or >8.5 mmol/L) due to genetically defined FCS to lower triglyceride levels and reduce the risk of pancreatitis, Class IIA, level of evidence B [39].

Olezarsen

Olezarsen is a triantennary GalNAc-conjugated ASO that targets APOC3 mRNA in the liver, leading to its degradation via RNase H1–mediated cleavage and subsequent reduction in apoC-III production [40]. It shares the same nucleotide sequence as volanesorsen but differs by the addition of the GalNAc3 moiety and its linker, which enables targeted hepatic delivery and localized action, allowing for lower dosing and injection volume.

The Phase 3 BALANCE trial evaluated subcutaneous olezarsen administered every 4 weeks in 66 patients with FCS, most of whom had a history of pancreatitis [33]. After 6 months, olezarsen 80 mg achieved least-squares means placebo-corrected percentage point reductions of 73.7% in apoC-III and 43.5% in triglycerides from baseline. After 12 months, olezarsen 80 mg achieved a least-squares mean placebo- corrected percentage point reduction in triglycerides of 59.4%. In the FDA analysis (https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/218614s000lbl.pdf?utm_source=chatgpt.com), when the reduction in triglycerides for the 80 mg dose was calculated with a placebo-washout imputation, the mean % treatment difference in triglycerides at 6 months was 42.5%. At 12 months, the mean % treatment difference in triglycerides was 57% (unpublished data).

Notably, acute pancreatitis was markedly reduced: only 1 of 22 patients receiving olezarsen 80 mg experienced a single episode (on day 357), compared to 11 episodes in 7 of 23 placebo-treated patients, beginning as early as day 9 (Fig. 1B). In a secondary endpoint, pooled patients treated with olezarsen 80 or 50 mg had a numerically lower incidence of acute pancreatitis compared with placebo (mean rate ratio, 0.12).

Suspected acute pancreatitis events were adjudicated by a blinded, independent clinical research organization using a committee of pancreatitis experts and the revised Atlanta classification and definitions by international consensus [41]. Because patients with recurrent pancreatitis are not always evaluated with the full complement of diagnostic tests and clinical diagnosis is common, the committee also assigned a graded level of evidence for events adjudicated as positive. Each event was classified as documented, probable, possible, unable to adjudicate, or no acute pancreatitis. Documented acute pancreatitis required at least two of the following: [1] abdominal pain strongly consistent with acute pancreatitis (acute onset of persistent, severe epigastric pain often radiating to the back); [2] serum lipase or amylase ≥ 3× the upper limit of normal; [3] characteristic findings on contrast-enhanced CT, MRI, or transabdominal ultrasonography. In BALANCE, 13 events were adjudicated as positive for acute pancreatitis with levels of evidence of 12 documented and 1 possible (Table 1).

Table 1 Details of adjudicated cases of pancreatitis in the balance trial based on revised Atlanta classification classification and definitions by international consensus

In 2024, olezarsen was approved by the FDA as an adjunct to diet for reducing triglyceride levels in adults with FCS. Importantly, genetic confirmation of FCS was not required for eligibility. Olezarsen is currently being investigated for its efficacy and safety in patients with SHTG (Essence-TIMI 73b; NCT05610280 [42] CORE-TIMI 72a; NCT05079919 [43], CORE2-TIMI 72b NCT05552326 [43].

Plozasiran

Plozasiran is a triantennary GalNAc3-conjugated siRNA that suppresses hepatic production and secretion of apoC-III [34, 44]. The Phase 3 PALISADE trial evaluated the efficacy and safety of subcutaneous plozasiran administered every 3 months in 75 patients with persistent chylomicronemia, including both genetically confirmed FCS and patients with symptomatic persistent chylomicronemia suggestive of FCS.

After 10 months, plozasiran 50 mg reduced placebo-adjusted median triglyceride and apoC-III levels by 53% and 93%, respectively. The 25 mg dose achieved comparable reductions of 59% and 91%, respectively [34]. In a pooled analysis, plozasiran also significantly reduced the incidence and delayed the onset of acute pancreatitis: 2 events occurred in 2 of 50 (4%) in the 25 mg plozasiran group, compared with 7 events in 5 of 25 (20%) placebo group (Fig. 1C).

Indirect Comparison of Olezarsen and Plozasiran on ApoC-III and Triglyceride Levels

Although no head-to-head trials have compared olezarsen and plozasiran, indirect comparisons, despite differences in study design and populations, can provide insight into their relative efficacy. Table 2 summarizes the key design features of the Balance [33] and PALISADE [34] trials. The Balance study enrolled patients with genetically confirmed FCS, with centralized adjudication of genetic causality in a core laboratory. In contrast, the PALISADE trial included both genetically confirmed FCS or presumed FCS, without noting the method of genetic determination or whether the testing was centralized or adjudicated. Furthermore, the PALISADE study reported median triglyceride values as the primary summary statistical analysis for triglyceride outcomes, versus mean levels in Balance. The Palisade analysis was placebo-adjusted by design (via the “median difference” estimand), but the reporting of the results does not always clearly reflect this.

Table 2 Key design features of the balance and PALISADE trials

To enhance comparability, placebo-adjusted median values from the olezarsen 80 mg and plozasiran 25 mg in PALISADE were aligned at similar timepoints (Table 3). ApoC-III reductions were nearly identical: − 87% at week 53 for olezarsen (95% CI: − 112, − 69) and − 87% at 10 months for plozasiran (95% CI: − 113, − 61). Triglyceride reductions were also similar, though numerically greater with plozasiran: − 60% (–92, − 28) vs. − 49% (–77, − 21) with olezarsen. These findings suggest comparable efficacy in lowering apoC-III and triglycerides, although formal statistical comparison is not possible due to lack of primary data for PALISADE, the presence of two populations of study subjects in PALISADE versus only genetically diagnosed FCS in Balance and methodological differences in data analysis and reporting. The most appropriate comparison would be to analyze change at similar timepoints in placebo-corrected mean or median values of apoC-III and triglycerides in the genetically confirmed FCS subjects in both studies.

Table 3 Comparison of changes in median (95% CI) apoC-III and triglyceride levels in the balance and PALISADE trials

Despite similar reductions in apoC-III, numerical differences in triglyceride lowering between groups is hypothesized to reflect differences in LPL activity in the study populations, although neither study measured LPL activity. For example, in the APPROACH trial of FCS, which enrolled subjects with both genetically confirmed and clinically confirmed FCS, similar reductions in apoC-III with achieved with volanesorsen as expected based on its mechanism. Both groups were able to achieve significant triglyceride reductions, but the triglyceride responses were modestly attenuated in the genetically diagnosed patients, suggesting that clinically diagnosed patients may recruit residual LPL activity that leads to more potent triglyceride reduction [45]. Consistent with this observation, in patients with moderate hypertriglyceridemia (triglyceride levels 150–500 mg/dL) where LPL activity is presumed to be normal, two phase 2 studies of olezarsen effects [46, 47] and the recent Essence-TIMI 73b trial showed robust triglyceride lowering. In Essence-TIMI 73b encompassing 1349 patients with mild hypertriglyceridemia (150–499 mg/dL), at 6 months the placebo-adjusted least-squares mean change in triglyceride level was − 58.4% points (95% confidence interval [CI], − 65.1 to − 51.7; P < 0.001) in the olezarsen 50-mg group and − 60.6% points (95% CI, − 67.1 to − 54.0; P < 0.001) in the olezarsen 80-mg group [25].

Targeting APOC3 To Reduce ASCVD

In individuals with triglyceride levels between 150 and 500 mg/dL, often seen in insulin resistance, metabolic syndrome, or type 2 diabetes, elevated apoC-III promotes accumulation of atherogenic remnant lipoproteins that are causally linked to ASCVD. Even modest triglyceride elevations are associated with subclinical atherosclerosis and vascular inflammation, particularly in statin-treated patients with normal LDL-C levels [4, 9].

Conventional triglyceride-lowering therapies—such as fibrates, niacin, and omega-3 fatty acids—modestly reduce apoC-III levels, limiting their efficacy in reducing ASCVD risk [18]. In contrast, therapies targeting APOC3 achieve greater reductions in triglycerides, remnant cholesterol, and TRLs, though they exert modest effects on LDL-C and apoB compared to statins or PCSK9 inhibitors. As such, they may be most effective when combined with LDL-C–lowering agents to address residual cardiovascular risk.

While APOC3 inhibition improves many lipid parameters, interpreting its impact on ASCVD risk is complicated by apparent increases in LDL-C, especially in individuals with impaired TRL clearance, such as those with FCS or severe hypertriglyceridemia. In these patients, baseline LDL-C is often artificially low due to defective VLDL remodeling [32, 33, 35, 45, 46]. As apoC-III is suppressed and TRL clearance improves, LDL particles may reappear or increase, reflecting a normalization of lipoprotein metabolism rather than a true rise in atherogenic burden [30, 33, 34, 36, 48]. Importantly, non–HDL-C and apoB levels usually decline modestly, supporting a net benefit. LDL-C changes with APOC3-targeted therapies should therefore be interpreted alongside broader markers such as apoB and remnant cholesterol.

Whether these favorable lipid changes translate into cardiovascular risk reduction remains an open question. Large outcome trials have yielded mixed results. PROMINENT and STRENGTH, which tested fibrates and high-dose omega-3 fatty acids respectively, failed to show ASCVD risk reduction despite lowering triglycerides [49, 50]. In contrast, REDUCE-IT demonstrated a 25% reduction in ischemic events with icosapent ethyl, despite only a modest 19.7% median triglyceride reduction—suggesting pleiotropic mechanisms beyond lipid lowering and/or adverse effects of the mineral oil placebo [51].

Notably, the apoC-III reductions achieved in STRENGTH (7.0%) and PROMINENT (27.8%) were substantially smaller than those observed with APOC3 loss-of-function mutations [49, 50], possibly explaining the lack of benefit. More potent suppression of apoC-III, as achieved with ASO and siRNA therapies, may be necessary to impact cardiovascular outcomes meaningfully.

Effects of APOC3 Inhibitors on Atherogenic Lipoproteins

Table 4 summarizes the effects of APOC3 inhibitors on atherogenic lipoproteins. ASO and siRNA therapies targeting apoC-III have shown consistent and robust reductions in TRLs, along with favorable changes in HDL-C and other atherogenic markers across multiple clinical trials.

Table 4 Effect of volanesorsen, olezarsen, and Plozasiran on lipid and lipoprotein profiles in patients with hypertriglyceridemia (≥ 150 mg/dL)

Volanesorsen demonstrated potent lipid-modifying effects in patients with hypertriglyceridemia. In a Phase 2 study [48], 13 weeks of treatment with volanesorsen 300 mg resulted in statistically significant mean percent change reductions in VLDL-C (–69.2%) and apoB-48 (–61.1%), along with a 45.7% increase in HDL-C compared to placebo. Although increases were observed in LDL-C and LDL-apoB, levels of non–HDL-C and total apoB remained unchanged. Volanesorsen also reduced the size of chylomicron–VLDL particles, suggesting enhanced clearance of atherogenic TRLs. Additionally, the drug lowered apoC-III levels across multiple lipoprotein classes, including apoB-containing particles, Lp(a), and apoA-I–containing HDL [19].

Olezarsen has demonstrated robust efficacy in reducing TRLs and atherogenic markers in high-risk populations. In a Phase 2 study involving patients with ASCVD or moderate hypertriglyceridemia with 80–90% on background statin therapy, olezarsen significantly reduced non–HDL-C, total apoB, and VLDL-C, while increasing HDL-C without affecting LDL-C levels [46]. Further analysis in a nuclear magnetic resonance study showed a 51% reduction in total TRL levels, a favorable shift in LDL particle size (186% increase in large LDL, 39% decrease in small LDL), and increased HDL particle counts [54]. Notably, 91% of patients treated with olezarsen 50 mg achieved triglyceride levels < 150 mg/dL, and 45% reached < 100 mg/dL [46]. Similar results were observed in the Bridge trial, where olezarsen 80 mg lowered triglycerides to < 150 mg/dL in over 93% of treated patients, compared to just 11.8% of those receiving placebo [47]. In the Essence-TIMI 73b study [25] changes in levels of apolipoprotein C-III, statistically significant placebo-adjusted reductions in both olezarsen doses were noted in VLDL-C (−57%), non-HDL-C (−22%), directly measured remnant cholesterol (−62 to 70%), apolipoprotein B (−15%), with no significant change in LDL-C (−1.1 to −1.5%).

Plozasiran demonstrated significant lipid-modifying effects in the Phase 2b MUIR trial [53]. Treatment increased HDL-C and reduced remnant-C, non–HDL-C, and total apoB. Up to 92% of patients receiving 25 or 50 mg quarterly achieved triglyceride levels < 150 mg/dL, compared to 21% in the placebo group. The reduction in non–HDL-C was primarily driven by decreases in remnant-cholesterol rather than LDL-C. In a recent meta-analysis in non-FCS patients [55], olezarsen and plozasiran both significantly reduced triglycerides, apoC-III, and non-HDL-C, and increased HDL-C. However, olezarsen did not significantly increase LDL-C, while plozasiran was associated with dose-dependent increases in LDL-C, particularly at higher doses. Whether these differences will be noted in phase 3 trials or impact hard CV outcomes remains unknown and requires dedicated cardiovascular outcomes trials to determine whether these lipid improvements translate into reduced events.

To evaluate the cardiovascular effects of apoC-III inhibition, an Essence-TIMI 73b trial substudy [25] is evaluating whether olezarsen-mediated reductions in apoC-III and triglycerides influence coronary plaque progression or stabilization using coronary CT angiography.

The effect of apoC-III in regulating triglyceride metabolism by inhibiting lipolysis and remnant clearance, and therapies targeting it—such as volanesorsen, olezarsen, and plozasiran—to lower triglycerides and reduce pancreatitis risk, with potential cardiovascular benefits is summarized in Fig. 2.

Fig. 2

Apolipoprotein C-III (apoC-III) regulates triglyceride metabolism by inhibiting lipolysis and remnant clearance, contributing to elevated triglyceride-rich lipoproteins (TRLs) and increased risk of acute pancreatitis and cardiovascular disease (CVD). Therapies targeting apoC-III, such as volanesorsen, olezarsen, and plozasiran, use ASO or siRNA technology to reduce apoC-III production and significantly lower triglyceride levels. These treatments have demonstrated reduced risk of acute pancreatitis and may potentially lower CVD risk, pending further clinical outcomes data

Safety and Tolerability

Nucleic acid therapies targeting APOC3 mRNA have generally reassuring safety profiles; however, administration-related adverse events (AEs) are reported across individual agents and the class. Injection-site reactions, most of which are characterized as mild, which are among the most common AEs across volanesorsen, olezarsen, and plozasiran trials. Hypersensitivity reactions have been also reported in patients treated with nucleic acid therapies. In non-GalNAc-modified volanesorsen, reversible decreases in platelet count were present. For GalNAc-modified ASOs, generally mild and transient declines in platelet counts have been noted, but these have not led to clinically meaningful bleeding or cessation of therapy. Overall, the proportion of patients experiencing a bleeding adverse event was similar across the olezarsen and placebo treatment groups. No clinically relevant changes have been noted in renal function.

Some patients with diabetes or prediabetes experienced worsening glycemic control during treatment with plozasiran [34, 53, 56]. However, assessments using the homeostatic model assessment of insulin resistance (HOMA-IR) did not indicate significant changes in insulin sensitivity [53, 56]. The underlying mechanisms for the observed deterioration in glycemic control are not yet elucidated [34, 53, 56]. The COMPASS trial in patients with SHTG with volanesorsen, but not APPROACH in FCS or BROADEN in FPLD, reported worsened glycemic control in patients with diabetes treated with volanesorsen [37]. In the olezarsen studies, no glucose