ANGPLT3 interfering RNA therapy reduces triglyceride levels in mixed hyperlipidemia

1. Zodasiran, an RNA interference (RNAi) therapy targeting angiopoietin-like 3 (ANGPTL3), resulted in a dose-dependent reduction in ANGPTL3 and triglyceride levels in patients with mixed hyperlipidemia.

2. Zodasiran also led to a dose-dependent reduction in other hyperlipidemic markers, including non-high-density lipoprotein cholesterol (non-HDLc) and low-density lipoprotein cholesterol (LDLc).

Evidence Rating Level: 1 (Excellent)

Study Rundown: Mixed hyperlipidemia is characterized by high levels of low-density and triglyceride-rich lipoproteins. While effective therapies exist to lower LDLc, there remains a significant cardiovascular risk with remnant cholesterol carried in triglyceride-rich particles such as chylomicrons and very low-density lipoproteins (VLDLs). ANGPTL3 regulates lipid metabolism, loss of function of which is associated with reduced levels of triglyceride-rich lipoproteins and LDLc and the corresponding risk of atherosclerotic cardiovascular disease. This is a phase 2b trial investigating zodasiran, a hepatocyte-targeting RNAi therapy targeting ANGPTL3, in adults with mixed hyperlipidemia. By 24 weeks, compared to placebo, zodasiran resulted in a dose-dependent reduction in the levels of ANGPTL3, triglyceride, non-HDLc, apolipoprotein B, and LDLc. Correspondingly, there was a correlation between the levels of ANGPTL3 and LDLc. At the highest 200mg dose, zodasiran was associated with a rise in glycated hemoglobin (HbA1c) levels among participants with pre-existing diabetes. The trial was limited by a short duration, with only two administrations and a predominantly White population. Nevertheless, these findings demonstrated the effectiveness of zodasiran in targeting ANGPTL3 and lowering atherogenic triglycerides and lipoproteins in adults with mixed hyperlipidemia.

Click here to read the study in NEJM 

In-Depth [randomized controlled trial]: This study was a placebo-controlled, randomized trial assessing the safety and efficacy of zodasiran in adults with mixed hyperlipidemia. Adult patients diagnosed with mixed hyperlipidemia who had been on a stable diet, statin regimen, and background medications were eligible for inclusion. Exclusion criteria included any other hepatocyte-targeting RNAi therapies, recent history of acute coronary syndrome or hemorrhagic stroke, planned bariatric surgery, uncontrolled thyroid disorder, and current steroid use. In total, 204 patients were randomized 3:1 to receiving subcutaneous zodasiran (at 50, 10, or 200mg) or placebo on day one and week 12 and followed for 36 weeks. The primary outcome was the percent change in fasting triglyceride level from baseline at week 24. Triglyceride level was reduced dose-dependent by zodasiran compared to placebo (difference in change vs. placebo -51 percentage points for 50mg, -57 percentage points for 100mg, and -63 percentage points for 200mg). ANGPTL3 level was also lowered significantly with zodasiran (difference in change vs. placebo -54 percentage points for 50mg, -70 percentage points for 100mg, and -74 percentage points for 200mg). Zodasiran also resulted in significant differences in change from baseline vs. placebo in other markers: for non-HDLc, -29 percentage points for 50mg, -29 percentage points for 100mg, and -36 percentage points for 200mg; for apolipoprotein B, -19 percentage points, -15 percentage points, and -22 percentage points, respectively; for LDLc, -16 percentage points, -14 percentage points, and -20 percentage points, respectively; and for HDLc, -12 percentage points, -22 percentage points, and -25 percentage points, respectively. In summary, these findings demonstrated the efficacy and safety of zodasiran in targeting ANGPTL3 and lowering atherogenic lipid levels among adults with mixed hyperlipidemia.

Image: PD

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