Hypertriglyceridemia (HTG) remains a significant clinical challenge because of its association with increased cardiovascular (CV) risk and acute pancreatitis.^1-3 The risk associated with triglyceride (TG) levels can be classified into different categories. Serum levels between 150 and 500 mg/dL are mainly linked to an elevated risk of cardiovascular disease (CVD).⁴ TG levels of 500-880 mg/dL increase the risk of CVD and pancreatitis, whereas levels >880 mg/dL significantly raise the risk of pancreatitis.⁴ Elevated levels of TG and triglyceride-rich lipoproteins (TRLs) are consistently linked with a higher risk of atherosclerotic cardiovascular disease (ASCVD). This association is due to remnant cholesterol in TRLs, which low-density lipoprotein cholesterol–targeted therapies do not effectively manage, leaving a gap in lipid-related ASCVD risk management.

The BRIDGE–TIMI 73a (Bridge–TIMI [Thrombolysis in Myocardial Infarction] 73a) trial investigators sought to explore this clinical question by assessing the effectiveness and safety of olezarsen in patients with HTG. Olezarsen is an antisense oligonucleotide (ASO) that specifically targets and degrades apolipoprotein C3 (APOC3) mRNA, thereby reducing the production of apolipoprotein C3 (ApoC3), which plays a crucial role in TG metabolism.⁵ ApoC3 inhibits lipoprotein lipase and hepatic uptake of TRLs.⁶ By reducing ApoC3, olezarsen enhances the breakdown and clearance of these lipoproteins, lowering plasma TG levels. This mechanism of action is supported by genetic evidence showing that individuals with loss-of-function mutations in the APOC3 gene have lower TG levels and a reduced risk of CVD.^4,7

This trial was a phase 2b, randomized, placebo-controlled, double-blind trial involving 154 adults with moderate HTG (150-499 mg/dL) and either elevated CV risk or severe HTG (≥500 mg/dL). Participants were divided into two groups (50 mg or 80 mg olezarsen) and randomized 3:1 to receive monthly subcutaneous injections of olezarsen or placebo for 12 months, with a 13-week follow-up. At baseline, participants had a median age of 62 years and median TG level of 241.5 mg/dL.

The primary outcome was the percent change in TG levels from baseline to 6 months (Figures 1, 2). Olezarsen significantly reduced TG levels, with the 50 mg dose achieving a 49% reduction and the 80 mg dose achieving a 53% reduction compared with placebo (p < 0.001 for both).⁶ Most patients achieved TG levels <150 mg/dL at 6 months, with sustained effects at 12 months.⁶ Key secondary outcomes showed significant improvements in several lipid parameters. Both doses of olezarsen reduced ApoC3 levels by 64% and 73%, significantly lowering very-low-density lipoprotein cholesterol, non−high-density lipoprotein cholesterol, and apolipoprotein (b) levels.⁶ These results highlight olezarsen's efficacy in treating mixed dyslipidemia by targeting multiple apolipoproteins contributing to CV risk.

Figure 1: Design of the BRIDGE–TIMI 73a Trial

Figure 2: Efficacy of Olezarsen in the BRIDGE–TIMI 73a Trial Data

The results of previous trials with volanesorsen, another ApoC3 ASO, also showed similar TG level reductions, but that agent had safety concerns related to thrombocytopenia.⁸ Olezarsen is a second-generation ASO that is conjugated with N-acetylgalactosamine, an amino sugar with a strong binding affinity for the asialoglycoprotein hepatic receptor; this allows much smaller doses of olezarsen to be administered with organ specificity, thereby reducing the potential for adverse effects.

Serious adverse events were infrequent and unrelated to the study drug. Increased liver enzyme levels were noted more often in the olezarsen groups; however, there were no signs of drug-induced liver injury, and significant bilirubin level elevations were absent.⁶ A small percentage of patients experienced decreases in estimated glomerular filtration rate and mild thrombocytopenia, particularly in the higher-dose group. Notably, the trial investigators reported no pancreatitis events.

Despite its promising results, the trial had a few limitations. It was relatively small and short in duration. The study's population may not fully represent the broader patient population with HTG, as specific subgroups were under-represented. Additionally, the trial did not include a diverse range of lipid-lowering therapies, which could affect the generalizability of the findings to real-world settings, in which patients often use multiple lipid-lowering agents. Finally, the trial did not evaluate the impact of olezarsen on CV events and death, necessitating further research to establish its long-term benefits and safety profile.

Olezarsen's effectiveness across a broad range of TG levels suggests its potential utility, not only for those at high CV risk, but also for those with conditions such as familial chylomicronemia syndrome (FCS) and multifactorial chylomicronemia syndrome. The BALANCE (A Study of Olezarsen Administered to Patients with Familial Chylomicronemia Syndrome) results corroborated this suggestion, demonstrating that olezarsen significantly reduces TG levels and substantially reduces acute pancreatitis events compared with placebo in patients with FCS. Specifically, the BALANCE trial data showed a 43.5% reduction in fasting TG levels with olezarsen 80 mg and only one acute pancreatitis episode among 43 patients receiving olezarsen; there were 11 episodes among 23 patients in the placebo group.⁹

Several ongoing phase 3 trials are being conducted to further assess the safety and effectiveness of olezarsen across a range of TG level elevations and primary endpoints. The CORE–TIMI 72a (A Study of Olezarsen Administered to Patients with Severe Hypertriglyceridemia–TIMI [Thrombolysis in Myocardial Infarction] 72a) trial investigators will study 540 patients and the CORE2 CS6–TIMI 72b (A Study of Olezarsen Administered Subcutaneously to Participants With Severe Hypertriglyceridemia–TIMI [Thrombolysis in Myocardial Infarction] 72b) trial investigators 390 patients with serum TG levels >500 mg/dL, with a primary endpoint of TG level lowering at 6 months; a hepatic magnetic resonance imaging substudy will evaluate changes in liver fat content.¹⁰ The ESSENCE CS9–TIMI 73b (A Study of Olezarsen [ISIS 678354] in Participants With Hypertriglyceridemia and Atherosclerotic Cardiovascular Disease, or With Severe Hypertriglyceridemia–TIMI [Thrombolysis in Myocardial Infarction] 73b) trial investigators will study approximately 1,320 patients with both moderate HTG (>200 mg/dL) and ASCVD, as well as those with severe HTG.¹⁰ The primary endpoint is TG level lowering at 6 months. This trial also includes a coronary computed tomographic angiography substudy to assess reduction in coronary plaque progression.¹⁰

References

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10. TIMI Study Group. Current Trials (TIMI Study Group website). Available at: https://timi.org/current-trials/. Accessed 09/30/2024.