EAS 2024 - In the ARCHES-2 trial, zodasiran reduced triglycerides, LDL-c, and other atherogenic lipids and lipoproteins at 24 weeks compared with placebo in patients with mixed hyperlipidemia and did not raise significant safety concerns.

This summary is based on the presentation of Robert Rosenson, MD (New York, NY, USA) at the EAS Congress 2024 - Zodasiran silences hepatic ANGPTL3 leading to deep and durable reductions in atherogenic lipids and lipoproteins in mixed hyperlipidemia patients: final results from ARCHES-2, double-blind period.

Introduction and methods

Mixed hyperlipidemia is a common disease that is characterized by elevated levels of low-density and triglyceride-rich lipoproteins. Despite potent lipid-lowering therapy, patients with mixed hyperlipidemia remain at high risk of ASCVD due to the presence of remnant cholesterol in atherogenic triglyceride-rich lipoproteins. Zodasiran (formerly known as ARO-ANG3) is a novel siRNA molecule that suppresses the expression of ANGPTL3, which encodes for angiopoietin-like protein 3. This protein is produced by hepatocytes and regulates lipid and lipoprotein metabolism by inhibiting lipoprotein and endothelial lipases and hepatic lipoprotein uptake.

The efficacy and safety of zodasiran were investigated in the ARCHES-2 (Study of ARO-ANG3 in Adults With Mixed Dyslipidemia) study, an international, double-blind, placebo-controlled, dose-ranging, phase 2b trial. In this RCT, 204 patients with mixed hyperlipidemia (triglycerides 150–499 mg/dL and either LDL-c ≥70 mg/dL or non–HDL-c ≥100 mg/dL) despite stable maximum-tolerated statin therapy were randomized in a 3:1 ratio to receive subcutaneous zodasiran (50 mg, 100 mg, or 200 mg) or placebo on day 1 and at week 12. All patients were followed up through week 36, after which they could enroll in the open-label extension phase.

The primary endpoint was the percent change in triglyceride levels from baseline to 24 weeks. Key secondary and exploratory endpoints included percent changes in ANGPTL3, non–HDL-c, LDL-c, apoB, remnant cholesterol, Lp(a), and HDL-c levels; percent change in liver fat fraction; and safety.

Main results

• At 24 weeks, the placebo-corrected least-squares (LS) mean percent change from baseline in triglyceride levels was −51 percentage points with zodasiran 50 mg, −57 percentage points with zodasiran 100 mg, and −63 percentage points with zodasiran 200 mg (all P<0.0001).
• Placebo-corrected LS mean percent changes from baseline to 24 weeks were –54 percentage points (zodasiran 50 mg), −70 percentage points (100 mg), and −74 percentage points (200 mg) for ANGPTL3 and –73 percentage points, –76 percentage points, and –82 percentage points, respectively, for remnant cholesterol (all P<0.0001) .
• In addition, zodasiran resulted in placebo-corrected LS mean percent reductions from baseline to 24 weeks in non–HDL-c (up to –36 percentage points), LDL-c (up to –20 percentage points), apoB (up to–22 percentage points), Lp(a) (up to –20 percentage points) (all P<0.05 ), and HDL-c (up to –25 percentage points; P<0.0001). • At 36 weeks, comparable results were observed, although the Lp(a) reduction was no longer significant.
• In a steatotic subgroup of 61 patients with a baseline liver fat fraction >8%, the median percent change in liver fat from baseline to 24 weeks was –27 percentage points with zodasiran 200 mg versus placebo (P<0.05).
• The 3 zodasiran dosing groups and the placebo group showed comparable adverse event rates, minimal changes in HbA1c levels, and no changes in platelet counts from baseline to 24 weeks.

Conclusion

In the ARCHES-2 trial, zodasiran reduced levels of triglycerides, ANGPTL3, LDL-c, and other atherogenic lipids and lipoproteins at 24 weeks compared with placebo in patients with mixed hyperlipidemia. The ANGPTL3 siRNA had an overall favorable safety profile. According to Dr. Rosenson, these findings “support the potential of zodasiran to treat residual ASCVD risk in patients with elevated triglyceride-rich lipoproteins.”

- Our reporting is based on the information provided at the EAS Congress 2024 -

The findings of this study were simultaneously published in N Engl J Med.