RNA Inhibitor Shows Early Efficacy, Safety in Adults With Mixed Dyslipidemia

The initial findings of a double-blind, placebo-controlled phase IIb study evaluating the efficacy and safety of investigational ARO-ANG3 in adults with mixed dyslipidemia were presented at the American Heart Association annual meeting.

In this exclusive MedPage Today video, presenter Robert S. Rosenson, MD, of the Icahn School of Medicine at Mount Sinai in New York City, discusses the ARCHES-2 study.

Following is a transcript of his remarks:

This phase II dose-ranging study evaluated the efficacy and safety of a small interfering RNA inhibitor to angiopoietin-like 3. Angiopoietin-like 3 is a protein predominantly expressed by the liver that inhibits lipoprotein lipase and endothelial lipase. This target has been evaluated with a human monoclonal antibody in patients with homozygous familial hypercholesterolemia, refractory heterozygous familial hypercholesterolemia, and patients with severe hypertriglyceridemia who have had acute pancreatitis.

Currently evinacumab [Evkeeza], a fully human monoclonal antibody, is FDA approved for patients with homozygous familial hypercholesterolemia. The current target, ARO-ANG3, is a small interfering RNA inhibitor that was evaluated in patients with mixed dyslipidemia -- specifically individuals who had triglycerides greater or equal to 200 mg/dL, elevated LDL [low-density lipoprotein] cholesterol greater or equal to 70 mg/dL, or non-HDL [high-density lipoprotein] cholesterol levels greater or equal to 100 mg/dL.

In this study of 160 subjects who were eligible after a diet run-in phase, we randomized them to treatment with ARO-ANG3 or placebo at three different doses.

We present the data for individuals that have completed 16 weeks of the study. We demonstrate reductions in triglycerides of about 60%, a dose-dependent reduction in LDL cholesterol up to 32%, reductions in apolipoprotein B, as well as remnant cholesterol.

These results are important for patients with mixed dyslipidemia, but importantly, unlike the Ionis-Pfizer compound, which used an antisense oligonucleotide, we report that ARO-ANG3 reduced hepatic fat by MRI.

As you may remember, the Ionis-Pfizer compound increased hepatic fat, increased transaminases, and that project was terminated.

So our study using an RNA inhibitor is important in many regards. Not only did we have greater efficacy on LDL cholesterol, apolipoprotein B, but we demonstrated a dose-dependent reduction in hepatic fat by MRI.

So we have demonstrated that this is an effective target that is safe and not only effective for reducing lipids, but it actually facilitates a reduction in hepatic fat. And this is important for those individuals with mixed dyslipidemia where non-alcoholic fatty liver disease is a major concern and presents a problem for lipid-lowering therapies, because many of the therapies make the transaminases levels worse. And again, our results show an improvement. And there was not a single patient who had increased transaminases that were sustained over the trial.

Comment