Zodasiran Demonstrated Safety, Efficacy in Treatment of Patients With Mixed Hyperlipidemia

Zodasiran (Arrowhead Pharmaceuticals) demonstrated clinically meaningful reductions in triglyceride levels at 24 weeks in patients with mixed hyperlipidemia, according to data from the phase 2b ARCHES-2 trial (NCT04832971). The trial results, published in the New England Journal of Medicine, show the efficacy of zodasiran as a therapeutic option for patients with hyperlipidemia carrying angiopoietin-like 3 (ANGPTL3) loss-of-function mutations.^1,2

At week 24, patients in the zodasiran cohort demonstrated substantial mean dose-dependent decreases from baseline in ANGPTL3 levels. Image Credit: © Thipphaphone - stock.adobe.com

Mixed hyperlipidemia is a heterogenous disorder characterized by elevated levels of total cholesterol, low-density lipoprotein (LDL) cholesterol (LDL-C) and triglycerides, and reduced levels of high-density lipoprotein (HDL) cholesterol (HDL-C). It is an inherited, genetic subgroup of a group of conditions called “familial hyperlipidemia,” which causes high LDL. Treatment for mixed hyperlipidemia can include lifestyle modifications surrounding diet and exercise, as well as agents such as statins, cholesterol-absorption inhibitors, or PCSK9 inhibitors.³

The identification of specific mutations has led to the development of promising molecular targets that help reduce levels of total cholesterol, LDL-C, HDL-C, and triglycerides, such as ANGPTL3 loss-of-function mutation. ANGPTL3 is a type of angiopoietin-like protein secreted in the liver. It is involved in the inhibition of lipoprotein lipase (LPL), which hydrolyzes the triglycerides carried in triglyceride-rich lipoproteins, and endothelial lipase to modulate HDL-C metabolism. Patients with ANGPTL3 loss-of-function mutations typically have lower levels of triglycerides, LDL-C, HDL-C, and non-HDL-C.^2,4

Zodasiran is an RNA interference (RNAi) therapy targeting expression of ANGPTL3 in the liver; it demonstrated favorable efficacy and safety in adults with mixed hyperlipidemia (fasting triglyceride level of 150 to 499 mg per deciliter and either an LDL cholesterol level of ≥70 mg per deciliter or a non-HDL cholesterol level of ≥100 mg per deciliter) in the double-blind, placebo-controlled, dose-ranging phase 2b ARCHES-2 trial. The researchers randomized 204 patients 3:1 to receive either subcutaneous injections of zodasiran (50, 100, or 200 mg) or placebo on day 1 and week 12 and were followed through week 36. The primary end point was the percent change in the triglyceride level from baseline to week 24.²

At week 24, patients in the zodasiran cohort demonstrated substantial mean dose-dependent decreases from baseline in ANGPTL3 levels (difference in change vs placebo, −54 percentage points with 50 mg, −70 percentage points with 100 mg, and −74 percentage points with 200 mg). Additionally, the researchers also observed significant dose-dependent decreases in triglyceride levels (difference in change vs placebo, −51 percentage points, −57 percentage points, and −63 percentage points, respectively).² Patients who received zodasiran also had differences in non-HDL-C levels (−29 percentage points with 50 mg, −29 percentage points with 100 mg, and −36 percentage points with 200 mg; for apolipoprotein B level, −19 percentage points, −15 percentage points, and −22 percentage points, respectively) and LDL-C levels (−16 percentage points, −14 percentage points, and −20 percentage points, respectively).²

The findings suggest the clinical significance of zodasiran as a treatment for patients with mixed hyperlipidemia. Continued research is needed to determine the long-term benefits and safety of the agent, as well as its potential use in combination therapies.

REFERENCES

1. Study of aro-ang3 in adults with mixed dyslipidemia (arches-2). ClinicalTrials.gov Identifier: NCT04832971. Updated April 18, 2024. Accessed October 7, 2024. https://clinicaltrials.gov/study/NCT04832971

2. Rosenson R, Gaudet D, Hegele R, et al. Zodasiran, an rnai therapeutic targeting angptl3, for mixed hyperlipidemia. N Engl J Med. May 29, 2024. doi:10.1056/NEJMoa2404147

3. What is hyperlipidemia? WebMD. March 4, 2024. Accessed October 7, 2024. https://www.webmd.com/cholesterol-management/hyperlipidemia-overview

4. Wang X, Musunuru K. Angiopoietin-like 3: from discovery to therapeutic gene editing. May 11, 2019. doi:10.1016/j.jacbts.2019.05.008