INTRODUCTION

Familial chylomicronemia syndrome (FCS) is an ultrarare disorder, with a prevalence estimated at approximately one to two cases per million individuals [1,2]. Its exceptionally low frequency has contributed to a longstanding lack of effective treatment options [3]. Conventional therapies, such as fibrates, omega-3 fatty acids, and statins, have shown limited efficacy in controlling triglyceride (TG) or remnant cholesterol levels, leaving affected individuals vulnerable to recurrent episodes of pancreatitis [4]. In 2019, however, approval of volanesorsen, an apolipoprotein CIII (apoCIII) inhibitor, by the European Union marked a turning point in FCS management and offered new hope to patients [5]. Since that milestone, multiple other APOC3-targeting agents have entered active development, demonstrating efficacy not only in individuals with FCS but also in those with severe hypertriglyceridemia and mixed dyslipidemia [6].

Homozygous familial hypercholesterolemia (HoFH) is another extremely rare genetic condition, most frequently caused by mutations in the low-density lipoprotein receptor gene (LDLR) [7]. Although conventional lipid-lowering therapies—including statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors—have been used in this population, their low-density lipoprotein cholesterol (LDL-C)–lowering effect is limited because they depend on LDLR-mediated pathways [8,9]. Consequently, individuals with HoFH remain at markedly increased risk of atherosclerotic cardiovascular disease (ASCVD) [10]. This unmet need has highlighted the importance of alternative therapeutic strategies, among which angiopoietin-like protein 3 (ANGPTL3) inhibitors provide a novel LDLR-independent mechanism for lowering LDL-C in HoFH [11,12].

This review outlines the mechanisms of action of APOC3 and ANGPTL3 inhibitors. This review also summarizes recent clinical and preclinical evidence for these agents, including both approved and investigational therapies, and discuss their potential role in future treatment strategies.

APOC3 INHIBITORS

Mechanism of action

APOC3 is a glycoprotein of approximately 8.8 kDa composed of 79 amino acids. It is primarily synthesized in the liver and exerts a critical influence on triglyceride metabolism by raising plasma levels of TG, TG-rich lipoproteins (TRLs), and remnant cholesterol through multiple mechanisms [13–15]. First, APOC3 inhibits lipoprotein lipase (LPL) activity, thereby impairing TRL clearance and increasing circulating remnant cholesterol and LDL particles. Second, it interferes with hepatic TRL uptake by disrupting the interaction between apolipoprotein E (apoE) and hepatic receptors such as LDLR and LDL receptor–related protein 1 (LRP1).

Therapeutic inhibition of APOC3 reduces TG levels by blocking these pathways. Supporting this concept, genetic studies have demonstrated that individuals with loss-of-function mutations in the APOC3 gene display reduced TG levels and lower risk of ASCVD [16]. Therapeutic strategies targeting APOC3 have since advanced to include both antisense oligonucleotide (ASO) and small interfering RNA (siRNA)-based modalities. A comparison of APOC3 inhibitors is presented in Table 1, while Fig. 1 illustrates the effects of APOC3 and ANGPTL3 inhibitors relative to baseline changes.

ASO-based APOC3 inhibitors

Volanesorsen

Volanesorsen is a 20-nucleotide, second-generation 2′-O-methoxyethyl (2′-MOE) chimeric ASO that targets APOC3 messenger RNA (mRNA) [17]. It has completed phase 3 clinical trials in FCS and is marketed under the trade name Waylivra.

The APPROACH trial (ClinicalTrials.gov identifier: NCT02211209) was a pivotal phase 3 randomized controlled trial that assessed the efficacy and safety of volanesorsen in 66 individuals with genetically confirmed FCS over a 52-week treatment period [18]. The primary endpoint was the percentage change in fasting TG levels at week 13. To minimize dietary variability, all participants underwent a 6-week diet stabilization period prior to randomization. More than 50% of participants were also receiving background lipid-lowering therapy, such as statins or fibrates. Despite these factors, volanesorsen produced a marked TG reduction from a baseline mean of 2,209 to 497 mg/dL, representing a 77% decrease (P<0.001). In contrast, the placebo group experienced an 18% increase in TG levels. During the extension period, participants who continued treatment for up to 24 months maintained a 50% reduction in TG levels. However, thrombocytopenia was reported as a notable adverse event. Platelet counts declined to <100,000/µL in about half of the treated participants, and to <25,000/µL in approximately 5%, though all cases recovered under close monitoring. Because of this safety concern, volanesorsen was approved in 2019 by the European Medicines Agency (EMA) for the treatment of FCS, but it did not receive approval from the US Food and Drug Administration (FDA).

The efficacy of volanesorsen has also been demonstrated in individuals with severe hypertriglyceridemia. In the COMPASS study (ClinicalTrials.gov identifier: NCT02300233), which included 114 participants, volanesorsen achieved a 71.2% reduction in TG levels, lowering mean values from 1,183 to 294 mg/dL [19].

Olezarsen

Olezarsen (Tryngolza) is a N-acetylgalactosamine (GalNAc)-conjugated ASO that targets hepatic APOC3 mRNA, thereby inhibiting APOC3 production. While it shares the same antisense mechanism as volanesorsen, conjugation with the GalNAc3 moiety enhances hepatic delivery, enabling lower dosing and longer duration of action. Importantly, this design substantially reduces the risk of thrombocytopenia. Olezarsen received FDA approval in 2024 for the treatment of FCS, making it the only FDA-approved APOC3 inhibitor in the United States.

The phase 3 BALANCE study (ClinicalTrials.gov identifier: NCT04568434) evaluated olezarsen in 66 individuals with FCS [20]. Participants were randomized in a 1:1:1 ratio to receive 50 mg every 4 weeks, 80 mg every 4 weeks, or placebo. Compared with placebo, the 80-mg regimen achieved a 43.5% reduction in TG levels (P<0.001), while the 50-mg regimen achieved a 22.4% reduction (P=0.08). Although the 50-mg dose yielded a modest effect, only the 80-mg dose provided a clinically robust reduction and is now the recommended regimen. In addition to TG lowering, both volanesorsen and olezarsen were associated with modest increases in high-density lipoprotein cholesterol (HDL-C; approximately 20%), which may provide additional cardioprotective benefit.

Of note, 71% of participants in the BALANCE study had a history of acute pancreatitis within the prior decade [20]. By week 53, there were 11 episodes of pancreatitis in the placebo group compared with just 1 episode in each olezarsen group, corresponding to an 88% relative risk reduction.

The phase 2b ARCHES-2 trial (ClinicalTrials.gov identifier: NCT04832971) further assessed olezarsen in 154 individuals with either moderate hypertriglyceridemia (150–499 mg/dL) and cardiovascular risk, or severe hypertriglyceridemia (≥500 mg/dL, approximately 10% of participants) [21]. In the group receiving 80 mg of olezarsen, TG levels were reduced by more than 50% compared with placebo (P<0.001).

siRNA-based APOC3 inhibitors

Plozasiran

Plozasiran (formerly known as ARO-APOC3) is an investigational siRNA therapeutic targeting APOC3, being developed for individuals with severe hypertriglyceridemia, mixed dyslipidemia, and FCS [22]. Compared with ASOs, siRNA therapy offers the advantage of more potent and durable gene silencing through RNA-induced silencing complex–mediated mRNA degradation, enabling robust effects at relatively low doses. Unlike volanesorsen or olezarsen, plozasiran is not yet approved but has completed a phase 3 trial for FCS (PALISADE study, ClinicalTrials.gov identifier: NCT05089084) and is currently under FDA review.

The PALISADE study, enrolled 75 individuals with FCS, with the primary outcome being the placebo-adjusted median change in TG levels at month 10 [23]. Plozasiran treatment reduced TG levels by 80% (from 2,008 to 409 mg/dL) with the 25-mg dose and by 78% (from 1,902 to 449 mg/dL) with the 50-mg dose, with no meaningful difference between the two regimens. These results suggest that the lower 25-mg dose achieves near-maximal efficacy, supporting more conservative dosing strategies. Since TG thresholds of <500 and <880 mg/dL are associated with reduced risk of acute pancreatitis [24,25], the proportions of patients reaching these targets at 10 months were 5% with placebo, 50% with 25 mg of plozasiran, and 46% with 50 mg of plozasiran. Among those on the 25-mg regimen, 75% achieved TG levels below 880 mg/dL [26]. Importantly, plozasiran reduced the risk of pancreatitis by 83% compared with placebo (P=0.03).

The phase 2b SHASTA-2 trial enrolled 229 individuals with moderate hypertriglyceridemia (500–4,000 mg/dL) and demonstrated TG reductions of 53.1% and 57.0% in the 25- and 50-mg plozasiran groups, respectively [27]. Building on these results, two phase 3 trials—SHASTA-3 (ClinicalTrials.gov identifier: NCT06347003) and SHASTA-4 (ClinicalTrials.gov identifier: NCT06347016)—are underway, both testing 25 mg every 12 weeks. Additionally, a phase 3 study in mixed dyslipidemia, MUIR-3 (ClinicalTrials.gov identifier: NCT06347133), is planned, and the CAPITAN trial will evaluate the effect of plozasiran on major adverse cardiovascular events, helping clarify its role in ASCVD risk reduction [28]. Cardiovascular outcome trials currently in progress are summarized in Table 2.

Despite its favorable lipid-lowering efficacy, concerns have emerged regarding potential hyperglycemia [29]. Increases in blood glucose have been noted in both FCS and mixed dyslipidemia populations, particularly among individuals with preexisting diabetes. In SHASTA-2, participants with diabetes demonstrated a mean hemoglobin A1c rise of 0.47% from baseline at week 24 [27].

ANGPTL3 INHIBITORS

Mechanism of action

ANGPTL3 is a 460–amino acid polypeptide predominantly expressed in the liver. A critical feature of ANGPTL3 is its regulation of lipid metabolism through pathways independent of the LDLR [30]. This property is particularly important in HoFH, where LDLR function is severely impaired or absent, making LDLR-independent therapies essential for LDL-C reduction. Inhibition of ANGPTL3 lowers LDL-C through these alternative pathways, and ANGPTL3 inhibitors are now approved for individuals with HoFH [31].

ANGPTL3 affects lipid metabolism through several mechanisms. It promotes hepatic production of very-low-density lipoprotein (VLDL) precursors and reduces LDLR-mediated LDL uptake by the liver, thereby elevating circulating LDL-C [31]. In addition, ANGPTL3 inhibits LPL activity, resulting in higher levels of chylomicrons, VLDL, and remnant cholesterol. Furthermore, it suppresses endothelial lipase activity, contributing to increased HDL-C [32]. Table 3 presents a comparison of ANGPTL3 inhibitors.

Evinacumab

Evinacumab (REGN1500, Evkeeza) is a fully human monoclonal antibody with an IgG4 constant region [33]. The EMA approved evinacumab in 2021 for individuals aged ≥12 years with HoFH [34], and in 2023 the FDA expanded approval to include children as young as 5 years, based on the ELIPSE HoFH trial (ClinicalTrials.gov identifier: NCT03399786) [35]. In the ELIPSE HoFH study, 65 individuals with genetically confirmed HoFH receiving maximally tolerated lipid-lowering therapy—including statins, PCSK9 inhibitors, or lipoprotein apheresis—were randomized to evinacumab (15 mg/kg intravenous [IV] every 4 weeks) or placebo. Compared to placebo, evinacumab (15 mg/kg IV every 4 weeks) resulted in a 49% reduction in LDL-C (−47.1% vs. +1.9%) [11]. This LDL-C–lowering effect is comparable to that achieved with LDL apheresis [36] and is substantially greater than reductions typically observed with PCSK9 inhibitors such as evolocumab (approximately 15%) [37] or high-dose statins (atorvastatin [80 mg] or rosuvastatin [40 mg], approximately 10%) [38,39], highlighting the remarkable efficacy of ANGPTL3 inhibition in this population [40,41].

In the open-label extension of ELIPSE HoFH, no cardiovascular events were reported over a median follow-up of 3.5 years, whereas 5 of 21 patients (24%) in a matched historical control group experienced 13 cardiovascular events over 4 years [42]. These data suggest a potential cardiovascular benefit of evinacumab in HoFH. However, to date, no large-scale randomized cardiovascular outcome trial of evinacumab has been initiated.

Zodasiran

Zodasiran is a GalNAc-conjugated RNA interference therapeutic designed to durably suppress ANGPTL3 expression in hepatocytes [43]. Unlike evinacumab, which requires intravenous infusion, zodasiran is administered subcutaneously, offering a more convenient dosing schedule and the possibility of at-home administration. Phase 2 studies demonstrated dose-dependent efficacy with minimal adverse events, supporting the initiation of a planned phase 3 trial. To date, clinical evidence comes from two phase 2 trials: GATEWAY (ClinicalTrials.gov identifier: NCT05217667) in individuals with HoFH and ARCHES-2 (ClinicalTrials.gov identifier: NCT04832971) in those with mixed dyslipidemia [12]. GATEWAY was an open-label study that enrolled 18 individuals with HoFH who were on stable, maximally tolerated lipid-lowering therapy (statins ± PCSK9 inhibitors or apheresis) and had baseline LDL-C >100 mg/dL. Participants received subcutaneous zodasiran at either 200 or 300 mg on day 1 and day 84. At week 24, LDL-C was reduced by 48.1% in the 200-mg group and 44.0% in the 300-mg group.

In ARCHES-2, 204 adults with mixed hyperlipidemia (fasting TG of 150–499 mg/dL and LDL-C ≥70 mg/dL or non–HDL-C ≥100 mg/dL) on maximally tolerated statin therapy were randomized to receive zodasiran at doses of 50, 100, or 200 mg [12]. TG levels decreased in a dose-dependent manner, with placebo-adjusted reductions of 51%, 57%, and 63%, respectively.

FUTURE DIRECTIONS

ASO- and siRNA-based therapies targeting APOC3 or ANGPTL3 have demonstrated superior efficacy and more favorable safety profiles than conventional lipid-lowering treatments. APOC3 inhibitors provide a critical therapeutic option for individuals experiencing recurrent pancreatitis despite dietary interventions, omega-3 fatty acids, or fibrates. Similarly, ANGPTL3 inhibitors achieve substantial LDL-C reduction in HoFH, a population in which conventional agents are insufficient, and may address residual ASCVD risk.

Despite these advances, no clinical trial has yet confirmed whether these agents reduce ASCVD events. Moreover, their extremely high cost, currently estimated at over US $400,000 to $500,000 annually, poses significant challenges to affordability and widespread access [44]. It is therefore imperative to develop cost-effective strategies that ensure these therapies are available to patients most in need. In addition, regulatory approval and importation have not yet occurred in Korea, leaving patients without access. The future introduction of these therapies into the Korean market is anticipated, which could expand treatment availability to individuals currently awaiting effective options.

CONCLUSIONS

APOC3 and ANGPTL3 inhibitors, developed using ASO and siRNA platforms, have reshaped the therapeutic landscape for rare dyslipidemias by achieving potent lipid-lowering effects. However, safety considerations remain, including thrombocytopenia observed with volanesorsen and hyperglycemia reported with plozasiran. These agents provide much-needed targeted strategies for managing FCS and HoFH, conditions in which conventional therapies are insufficient. Yet their ultimate value in reducing ASCVD events must still be established through dedicated cardiovascular outcome trials. Furthermore, high cost and limited global accessibility, especially in regions such as Korea, where these agents are not yet available, highlight the urgent need for strategies that ensure long-term affordability and equitable access worldwide.

ARTICLE INFORMATION

Conflicts of interest

The author has no conflicts of interest to declare.

Funding

The author received no financial support for this study.

Fig. 1.

Comparison of the effects of (A, B) apolipoprotein CIII (APOC3) inhibitors and (C) angiopoietin-like protein 3 (ANGPTL3) inhibitors based on baseline changes. (A) Familial chylomicronemia syndrome. (B) Hypertriglyceridemia. (C) Homozygous familial hypercholesterolemia. LDL-C, low-density lipoprotein cholesterol; TG, triglyceride.

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Figure & Data

References

Citations

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• Efficacy and Safety of Apolipoprotein C‐III Inhibitors in Hypertriglyceridemia: A Network Meta‐Analysis of Randomised Controlled Trials
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