Steep LDL Cholesterol Reductions With ANGPTL3 siRNA in HoFH

MANNHEIM, Germany — A novel drug that targets production of a liver protein involved in lipid metabolism appears to markedly reduce low-density lipoprotein (LDL) cholesterol levels for patients with homozygous familial hypercholesterolemia (HoFH), suggest results from the phase 2 GATEWAY trial.

The research was presented at the European Atherosclerosis Society (EAS) 2023 congress on May 23.

The drug, ARO-ANG3 (Arrowhead Pharmaceuticals), is a hepatocyte-targeted small interfering ribonucleic acid (siRNA) designed to silence expression of the angiopoietin-like protein 3 (ANGPTL3) gene.

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

The trial involved 18 patients with HoFH who were already receiving standard-of-care lipid-lowering therapy. The patients were randomly assigned to receive two injections 12 weeks apart of either a 200-mg or a 300-mg dose of ARO-ANG3.

The current interim analysis showed that after 20 weeks, LDL cholesterol levels decreased by 48.1% and 44.0%, respectively, in the two groups. There were similar reductions in other lipids.

“If you look at the curves, they’re going down, down, down,” study presenter Frederick J. Raal, MMed, PhD, distinguished professor and director of the Carbohydrate and Lipid Metabolism Research Unit, University of the Witwatersrand, Johannesburg, South Africa, told | Medscape Cardiology.

Anticipating full efficacy analysis, he said the current reductions are such that “you can predict that at 24 weeks, they’re going to be very, very similar.”

Crucially, there were few adverse events, with no drug discontinuations or reductions and no indication of an impact on liver function.

Moreover, “from the patient’s point of view,” Raal said, the attraction of ARO-ANG3 is that “instead of coming in once a month for an IV infusion,” as required by some other treatments, 3-monthly subcutaneous injections with this drug “looks pretty good.”

He noted, however, that the therapy does not result in complete inhibition of ANGPTL3 production but reduces it to a “drip,” and so it will likely complement existing lipid-lowering therapies.

Raal said that although the 300-mg dose is not “turning off the tap better than 200 mg,” the efficacy and safety results were very similar, and the company is likely to pick the 300-mg dose at a frequency of 3 months for future studies.

Following presentation of the interim analysis of this phase 2 trial, Arrowhead Pharmaceuticals announced that they are currently planning a phase 3 study “to further investigate ARO-ANG3” and that the company “intends to conduct a meeting with regulatory authorities in the second half of 2023 to discuss the proposed study design.”

“Interesting Protein”

Approached for comment, G. Danilo Norata, PhD, professor, Department of Pharmacological and Biomolecular Sciences, University of Milan, Italy, said that ANGPTL3 is “emerging as an interesting protein in the field of dyslipidemia.”

He told | Medscape Cardiology that the initial genetic evidence from studies published over 10 years ago suggested that loss-of-function mutations are associated with hypolipidemia, “which is intriguing compared to other targets.

“This is why there are several strategies aimed at testing if the inhibition or silencing of ANGPTL3 will translate into clinical benefits.”

Norata pointed out there are at least two approaches to targeting the protein, one a monoclonal antibody, evinacumab (Evkeeza, Regeneron Pharmaceuticals), that reduces the circulating form of ANGPTL3.

Evinacumab was approved by the US Food and Drug Administration in 2021 for use in addition to other cholesterol-modifying medications for patients with HoFH who are aged 12 years and older; earlier this year, the indication was extended to cover patients aged 5 to 11 years.

The other approach is that of gene silencing. Vupanorsen was an antisense oligonucleotide that targeted ANGPTL3. It was developed by Pfizer and was tested in patients with hypertriglyceridemia.

“It was successful, but they decided to stop the development of the product due to some side effects in the liver,” Norata said. “So, this is relevant for all new compounds in the field…to really look into the safety,” particularly for signs of liver toxicity.

In presenting the data, Raal explained that ARO-ANG3, which is administered subcutaneously, inhibits and degrades ANGPTL3 mRNA, leading to “deep and durable silencing of the ANGPTL3 gene, while avoiding off-target effects.”

He said that, considering the example of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, monoclonal antibodies “mop up 100% of the PCSK9 in the bloodstream, but that requires frequent injections.”

The alternative is to stop the production of the protein in question. There are two ways of doing that, he said, antisense oligonucleotides, “or best is probably…siRNA.”

The reason siRNA is better “is it gets into a little thing in the cell called the RISC complex and recirculates, so that means you can give the dose much less frequently.” In other words, “you’ve got guaranteed compliance. It’s like a vaccine.”


The GATEWAY trial involved patients with HoFH that was confirmed on genetic testing or who had received a clinical diagnosis. Participants’ mean fasting baseline LDL cholesterol level was >2.6 mmol/L while receiving standard-of-care lipid-lowering treatment, including apheresis. They underwent a screening period of up to 8 weeks.

They were then randomly assigned to receive either 200 mg or 300 mg of ARO-ANG3 on day 1 and week 12. They were then followed up to week 36, after which began a 24-month open-label extension period.

Eighteen patients were randomly assigned. The mean age of the patients in the 200-mg group was 49.6 years; in the 300-mg group, it was 36.3 years. The proportion of women was 77.8% and 66.7%, respectively.

The mean baseline LDL cholesterol level was 8.9 mmol/L in the 200-mg group and 11.1 in the 300-mg group.

The current interim analysis included data on 17 patients who had completed 20 weeks of the study. The cutoff date for lipid measurements was April 17, 2023.

As expected, ARO-ANG3 led to large reductions in circulating ANGPTL3 levels. There was an 82.7% reduction with the 200-mg dose and an 80.1% reduction for patients given 300 mg of the drug.

By week 20, LDL cholesterol levels had decreased by a mean of 4.4 mmol/L from baseline with the 200-mg dose. For patients in the 300-mg group, levels decreased by 5.0 mmol/L. Relative reductions were of 48.1% and 44.0%, respectively.

The results also showed that apolipoprotein B levels decreased by 39.2% from baseline with the 200-mg dose and by 34.5% in the 300-mg group. Triglycerides fell by 38.8% and 28.3%, respectively.

In addition, high-density lipoprotein cholesterol levels decreased with ARO-ANG3, falling by 29.2% from baseline to week 20 in the 200-mg group and by 32.7% for patients given the 300-mg dose.

Raal pointed out that this effect of ANGPTL3 inhibition is “consistent with human genetic data” from previous studies.

Regarding safety, he said that there were no treatment-related adverse events that led to drug discontinuation, dose interruptions, study withdrawal, or death. There were no adverse events related to elevated alanine aminotransferase levels.

Eight (44%) patients experienced treatment-related adverse events, including one serious event. These included two (11%) cases each of dizziness, injection site pain, and nasopharyngitis.

There was also one case of second-degree atrioventricular block in a patient with a history of extensive ASCVD, which required treatment with a pacemaker, but it was considered unrelated to the study drug.

The study was sponsored by Arrowhead Pharmaceuticals. Raal has relationships with Amgen, Sanofi-Adventist, Regeneron, Novartis, LIB-Therapeutics, and Arrowhead Pharmaceuticals.

European Atherosclerosis Society (EAS) 2023: Abstract SS124/1495. Presented May 23.

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