1. In this randomized controlled trial, 80 mg of olezarsen, but not 50 mg, significantly reduced triglyceride levels compared to placebo after six months in familial hyperchylomicronemia syndrome (FCS) patients.

2. The overall incidence of acute pancreatitis was lower in patients who received olezarsen compared to placebo at 53 weeks.

Evidence Rating Level: 1 (Excellent)

Study Rundown: FCS is a rare autosomal recessive metabolic disorder characterized by high levels of plasma triglycerides. It is caused by biallelic defects in the lipoprotein lipase (LPL) gene or related genes needed for LPL function. Loss of LPL activity results in decreased ability to hydrolyze triglycerides to lipoproteins, leading to severe hypertriglyceridemia. FCS can lead to hypertriglyceridemia-induced acute pancreatitis, which is associated with high morbidity and mortality. Loss-of-function variants in apolipoprotein C-III (APOC3), a liver-made glycoprotein abundant in chylomicrons, are associated with lifelong low plasma triglyceride levels. Volanesorsen, an antisense oligonucleotide that targets APOC3 messenger RNA (mRNA), has been used in the United Kingdom and Brazil to treat FCS. Olezarsen, which is volanesorsen conjugated with triantennary N-acetylgalactosamine (GalNAc3) for facilitated entry into the hepatocyte nucleus where APOC3 mRNA is synthesized, is an investigational antisense oligonucleotide that is expected to permit lower dosing than volanesorsen. This trial investigated the efficacy and safety of olezarsen in patients with FCS. Overall, it showed that 80 mg of olezarsen, but not 50 mg, led to a significant reduction of triglyceride levels compared to placebo after six months. In addition, acute pancreatitis was lower in patients who received either olezarsen dose than placebo at 53 weeks. The generalizability of the trial results is limited by its small sample size and lack of racial diversity represented in the study population.

Click to read the study in NEJM

In-Depth [randomized controlled trial]: This was a double-blind, placebo-controlled, phase 3 trial that evaluated the efficacy and safety of olezarsen in the treatment of FCS. Patients who were 18 years of age or older and had fasting triglyceride levels of 880 mg per deciliter or higher and suspected FCS underwent screening and genetic testing. Enrolled patients were randomly assigned in a 1:1 ratio to receive either an 80 mg or 50 mg dose of olezarsen, and then within each dose cohort, randomly assigned in a 2:1 ratio to receive the assigned dose or placebo. The primary outcomes were the difference in percent change in the fasting triglyceride level from baseline to six months in the 80-mg olezarsen group versus placebo and the 50-mg olezarsen group versus placebo. Among 144 patients who underwent screening, 66 underwent randomization (22 in the 80-mg olezarsen group, 21 in the 50-mg olezarsen group, and 23 in the placebo group). The mean (± standard deviation) triglyceride level was 2630±1315 mg per deciliter, and 55 patients had biallelic loss-of-function variants in LPL. The difference in triglyceride levels at 6 months between the 80-mg olezarsen and placebo groups was significant at -43.5 percentage points (95% confidence interval [CI], -69.1 to -17.9; p<0.001), although the difference between the 50-mg olezarsen and placebo groups was not significant at -22.4 percentage points (95% CI, -47.2 to 2.5; p=0.08). The mean change in the fasting APOC3 level from baseline to 6 months was -73.7 percentage points (95% CI, -94.6 to -52.8) between the 80-mg olezarsen and placebo groups and -65.6 percentage points (95% CI, -82.6 to -48.3) between the 50-mg olezarsen and placebo groups. By 53 weeks, one episode of acute pancreatitis occurred in each olezarsen group, and 11 episodes occurred in the placebo group. In summary, 80 mg of olezarsen, but not 50 mg, significantly reduced triglyceride levels more than placebo in patients with FCS.

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