Gene Silencing Benefit of Zodasiran in Hyperlipidemia

LYON, France — The drug zodasiran (formerly ARO-ANG3), which targets the production of a liver protein, substantially lowers triglyceride and a range of lipoprotein levels in patients with mixed hyperlipidemia who are stable on optimal statin therapy, according to ARCHES-2 study investigators.

The hepatocyte-targeted small interfering (si) RNA was designed to silence the expression of the ANGPTL3 gene.

“The reductions in serum lipids and lipoproteins and the favorable safety profile seen in ARCHES-2 support the potential for zodasiran to treat residual atherosclerotic cardiovascular disease in patients with elevated triglycerides,” said Robert S. Rosenson, MD, director of metabolism and lipids at the Mount Sinai Health System in New York City.

“These data support the further development of zodasiran in phase 3 programs, including a cardiovascular outcomes trial,” he said at the European Atherosclerosis Society (EAS) 2024 while reporting the findings, which were simultaneously published in TheNew England Journal of Medicine.

The ANGPTL3 protein regulates metabolism by inhibiting lipoprotein and endothelial lipases. Loss-of-function variants have been shown to increase lipase activity, leading to reductions in lipid levels and in the risk for atherosclerotic cardiovascular disease, with no apparent adverse effects.

The data are “very interesting and compelling,” said session co-chair Bart Staels, PhD, director of Inserm Unit UMR 1011, which has laboratories at the Lille Pasteur Institute and the University of Lille in France.

The combination of reductions in triglycerides, low-density lipoprotein (LDL) cholesterol, remnant cholesterol, and apolipoprotein B, among others, should be “based on our current knowledge, decrease the cardiovascular risk of patients with mixed dyslipidemia quite significantly,” he said.

“Moreover, the decrease remained effective even 24 weeks after the last treatment,” said Staels, who was not involved in the study.

Less Liver Fat 

The reductions in liver fat content seen with zodasiran are “also very interesting,” and “raise the possibility of a positive effect on metabolic dysfunction-associated steatotic liver disease,” he said.

Although the trial was “not designed to test efficacy in reducing the risk of coronary artery disease,” the evidence points toward “fewer coronary artery disease events,” Pradeep Natarajan, MD, from the Division of Cardiology at Massachusetts General Hospital and Harvard Medical School in Boston, writes in an accompanying editorial.

However, the progress seen with zodasiran and other siRNA-based therapies “highlights the importance of studying diverse populations because exceptional alleles are variably prevalent across racial and ethnic groups,” he pointed out.

“Increasingly, massive intentionally diverse biobanks, such as the National Institutes of Health All of Us research program, are enabling the critical search of such exceptional alleles at an unprecedented scale,” Natarajan explained. “Inclusive human genetic research benefits us all.”

The earlier phase 2 GATEWAY study showed that zodasiran markedly reduced LDL cholesterol levels in patients with homozygous familial hypercholesterolemia by 44%-48.1%, depending on the dose given.

The phase 2b ARCHES-2 trial involved patients with mixed hyperlipidemia who had fasting triglyceride levels of 150-499 mg/dL and either an LDL cholesterol level ≥ 70 mg/dL or a non–high-density lipoprotein (HDL) cholesterol level ≥ 100 mg/dL. They were also receiving stable optimal statin therapy.

After a run-in period of up to 6 weeks, the participants were randomly assigned to zodasiran 50 mg, 100 mg, or 200 mg or placebo, with injections given at baseline and at week 12. The primary endpoint was the percentage change in triglyceride levels from baseline to week 24.

All study participants were then offered the opportunity to enroll in an open-label extension after 36 weeks of follow-up.

Open-Label Extension

Of the 204 patients randomly assigned to the extension study, 47% were women, 96% were White, the mean age was 61 years, and the average body mass index was 33. There was an “imbalance” in the proportion of patients with type 2 diabetes, which ranged from 37% to 49% in the treatment groups, Rosenson reported.

As expected, all three doses of zodasiran were associated with “substantial and durable” reductions in ANGPTL3 levels from baseline, with a least-squares mean difference relative to placebo at 24 weeks of 54% with the 50-mg dose, 70% with the 100-mg dose, and 74% with the 200-mg dose, which were largely retained at 36 weeks.

These reductions were mirrored by dose-dependent reductions in triglycerides from baseline, with a least-squares mean difference relative to placebo at 24 weeks of 51% with the 50-mg dose, 57% with the 100-mg dose, and 63% with the 200-mg dose (P

Similar reductions were seen in levels of remnant cholesterol, non-HDL cholesterol, LDL cholesterol, and apolipoprotein B levels, although the decreases were less consistent and less likely to be maintained out to 36 weeks.

Among the 61 patients with hepatic steatosis greater than 8% at baseline, zodasiran was associated with a median liver fat decrease relative to placebo at week 24 of 10% with the 50-mg dose, 16% with the 100-mg dose, and 27% with the 200-mg dose.

For patients who received zodasiran, decreases in HDL-cholesterol levels ranged from 12.0% to 24.5% at week 24, and “consistent with the mechanism of blocking endothelial lipase, [they] reported a non–dose-dependent reduction in lipoprotein(a) of 7.0% to 20.0%,” Rosenson said.

The “safety results are as expected for this population,” and there were “no changes in platelet concentrations” and “minimal” changes in A1c levels, he reported.

Apart from one death in the placebo group, the 0%-10% of patients who experienced any serious adverse event either recovered or the issue resolved. Overall, zodasiran has a “favorable safety profile,” and “all treatment-emergent adverse events were manageable,” Rosenson said.