Zodasiran Reduces Triglycerides, ANGPTL3 in Mixed Hyperlipidemia in ARCHES-2 Trial

Robert Rosenson, MD
Credit: Cura Foundation

Results of a phase 2 trial in patients with mixed hyperlipidemia suggest use of zodasiran, an RNA interference therapy targeting angiopoietin-like 3 (ANGPTL3) inhibition, was well-tolerated and contributed to significant decreases in triglyceride levels at 24 weeks.

Presented by Robert Rosenson, MD, at the European Atherosclerosis Society 2024 annual meeting, results of the study indicate use of the agent was associated with significant improvements in triglyceride levels, with use associated with dose-dependent reductions in triglycerides up to 63% with the greatest dose of zodasiran, but also nominal improvements other lipid parameters, including non-HDL-C, apolipoprotein B, and LDL-C.

“Our study represents one of the first trials of an RNA inhibitor of ANGPTL3 with advantages like durable gene silencing and infrequent dosing,” said Rosenson, professor of Medicine (Cardiology) at the Icahn School of Medicine at Mount Sinai and director of Lipids and Metabolism for the Mount Sinai Health System, in a press release from Mount Sinai. “For patients with mixed hyperlipidemia and persistent elevations in LDL cholesterol and non-HDL cholesterol, zodasiran could expand the opportunities for lowering “bad” cholesterol beyond conventional therapies such as statins, potentially leading to more favorable outcomes for patients.”

Named ARCHES-2, the double-blind, placebo-controlled, dose-ranging phase 2b trial enrolled adults with mixed hyperlipidemia, which was defined as a fasting triglyceride level of 150 to 499 mg/dL and either an LDL cholesterol level of 70 mg/dL or a non-HDL cholesterol level of 100 mg/dL or greater. Additional inclusion criteria for the study required patients to have been following a stable diet for at least 2 weeks, be receiving a stable statin regimen, unless unable to take statins, for at least 4 weeks, and be receiving stable background medications.

These patients were randomized in a 3:1 ratio to receive subcutaneous injections of zodasiran at doses of 50, 100, or 200 mg or placebo therapy on day 1 and week 12 and were followed through week 36. The primary outcome of interest for the trial was the percent change in triglyceride levels from baseline to week 24.

In total 204 patients underwent randomization and 191 completed the double-blind treatment period. At baseline, this cohort had a mean age of 61 years, mean BMI of 33 kg/m2, mean triglyceride level of 246 mg/dL, mean remnant cholesterol levels of 48 mg/dL, mean non-HDL cholesterol levels of 46 mg/dL, and mean LDL cholesterol level of 97 mg/dL. As it relates to background medication use, at baseline, 96% were receiving statin therapy, 1% were receiving PCSK9 inhibitors, and 21% were receiving fibrates.

Upon analysis, results indicated use of zodasiran was associated with significant and dose-dependent least-squares mean differences in triglyceride levels as compared with placebo at 24 weeks, with placebo-adjusted reductions of -51 percentage points (95% Confidence Interval [CI], -62 to -41), -57 percentage points (95% CI, -67 to -46), and -63 percentage points (95% CI, −74 to −53) with the 50 mg, 100 mg, and 200 mg doses, respectively. Investigators highlighted these were sustained out to week 36, with placebo-adjusted differences in triglyceride levels of −34 percentage points (95% CI, −45 to −24), −38 percentage points (95% CI, −49 to −27), and −51 percentage points (95% CI, −62 to −41) with the 50 mg, 100 mg, and 200 mg doses, respectively.

Further analysis suggested use was associated with dose-dependent decreases from baseline in ANGPTL3 levels, with placebo-adjusted difference in change of −54 (95% CI, −62 to −46) percentage points, −70 (95% CI, −78 to −62) percentage points, and −74 (95% CI, −81 to −66) percentage points with the 50 mg, 100 mg, and 200 mg doses, respectively. Investigators pointed out these reductions were strongly correlated with triglyceride levels (Pearson correlation coefficient, 0.69).

Analysis of the trial’s secondary outcomes of interest revealed the following placebo-adjusted changes:

Non-HDL cholesterol level:

−29 percentage points with 50 mg

−29 percentage points with 100 mg

−36 percentage points with 200 mg

Apolipoprotein B level:

−19 percentage points with 50 mg

−15 percentage points with 100 mg

−22 percentage points with 200 mg

LDL-C level:

−16 percentage points with 50 mg

−14 percentage points with 100 mg

−20 percentage points with 200 mg

“It’s our contention that based on these promising results, further studies are warranted to determine the potential of zodasiran, an investigational drug has the potential to reduce the risk of cardiovascular events in a broad range of patients through a single therapy that targets all the lipoprotein fractions,” Rosenson added.

References:

1. Rosenson RS, Gaudet D, Hegele RA. Zodasiran, an RNAi Therapeutic Targeting ANGPTL3, for Mixed Hyperlipidemia. New England Journal of Medicine. Published online May 29, 2024. doi:10.1056/NEJMoa2404147
2. Mount Sinai Health System. RNA inhibitor is shown safe and effective in reducing a wide range of cholesterol and triglyceride levels in the blood in Mount Sinai-led clinical trial. Mount Sinai Health System. May 29, 2024. Accessed May 30, 2024. https://www.mountsinai.org/about/newsroom/2024/rna-inhibitor-is-shown-safe-and-effective-in-reducing-a-wide-range-of-cholesterol-and-triglyceride-levels-in-the-blood-in-mount-sinailed-clinical-trial.