Zodasiran Trial Lowers Cholesterol in Mixed Dyslipidemia

The Mount Sinai researchers discovered that the RNA interference (RNAi)-based therapy zodasiran was a potentially promising option for significantly reducing the number of atherogenic lipoproteins while requiring less frequent dosing than conventional therapies. They also observed encouraging preliminary results regarding safety and efficacy in clinical trials.

Our study represents one of the first trials of an RNA inhibitor of ANGPTL3 with advantages like durable gene silencing and infrequent dosing. 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.” – Robert Rosenson, MD, Lead Author, 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

The accumulation of fats in the blood is the hallmark of mixed hyperlipidemia, which is frequently inherited. People who have this illness may be overweight and at a higher risk of developing diabetes or prediabetes.

Researchers saw significant decreases in all lipid level parameters tracked in the phase 2b global trial (ARCHES-2) involving 204 patients with mixed hyperlipidemia who received zodasiran (50, 100, and 200 mg) and background therapy of standard-of-care medications, including statins. These included reductions in LDL cholesterol of up to 20 percent, non-HDL cholesterol of up to 36 percent, remnant cholesterol of 73 to 82 percent, and triglycerides of 54 to 74 percent when compared to placebo. The quantity of “leftover” or remnant very-low-density lipoprotein (VLDL) particles is measured by remnant cholesterol. It is calculated by summing the levels of HDL and LDL and deducting that amount from the person’s total cholesterol.

Because remnants can contain up to four times more cholesterol per particle than LDL, lowering remnant cholesterol is very crucial. Furthermore, other studies have shown a link between higher residual cholesterol and a higher risk of cardiovascular disease. Based on previous genetic research, the Mount Sinai researchers hypothesized that the amount of leftover cholesterol reduction shown by zodasiran in their study could correspond to a 20 percent reduction in recurrent major cardiac episodes.

Additionally, the ARCHES-2 study discovered that zodasiran was successful in reducing the body’s level of apolipoprotein B, a lipid-transporting protein that has been connected to a higher risk of heart disease at elevated levels.

“In contrast to fibrates and fish oils, zodasiran lowers apolipoprotein B and thus may be a more promising potential therapy for reducing the risk of cardiovascular events,” Dr. Rosenson notes.

The U.S. Food and Drug Administration has approved evinacumab, a fully human monoclonal antibody against the ANGPTL3 protein, to treat patients with homozygous familial hypercholesterolemia (HoFH). The results of this study in patients with mixed hyperlipidemia build on previous attempts to modulate ANGPTL3. “It’s our contention,” asserts Dr. Rosenson, “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.”

Arrowhead Pharmaceuticals, Inc. (Pasadena, CA) funded this trial.

For more information: Zodasiran, an RNAi Therapeutic Targeting ANGPTL3, for Mixed Hyperlipidemia,  The New England Journal of Medicine, doi.org/10.1056/NEJMoa2404147