Arrowhead Pharma Reports New Phase 2 Zodasiran Data in Mixed Hyperlipidemia Patients

Arrowhead Pharmaceuticals, Inc. recently unveiled the outcomes of its Phase 2b ARCHES-2 trial, which evaluated the investigational RNAi therapeutic, zodasiran, in patients suffering from mixed hyperlipidemia. The study demonstrated that zodasiran significantly reduced levels of triglycerides and atherogenic triglyceride-rich lipoproteins across all dosages at the 24-week mark. The findings were disclosed at the European Atherosclerosis Society's (EAS) 92nd Congress and were published in the New England Journal of Medicine.

Dr. Bruce Given, Interim Chief Medical Scientist at Arrowhead, highlighted the significance of ANGPTL3 as a target for RNAi-based gene silencing strategies. He emphasized that genetic variants causing a loss of ANGPTL3 function are linked to heightened activity of lipoprotein lipase and endothelial lipase, leading to lower plasma lipoprotein levels and a reduced risk of atherosclerotic cardiovascular disease (ASCVD). This genetic insight underpins the potential of zodasiran to mitigate the residual ASCVD risk in patients with elevated triglyceride-rich lipoproteins.

Dr. Robert Rosenson, Principal Investigator for the ARCHES-2 study and a professor at the Icahn School of Medicine at Mount Sinai, echoed these sentiments. He pointed out the substantial lipid and lipoprotein reductions observed in the study and advocated for further Phase 3 trials to ascertain if zodasiran can replicate these genetic benefits and lower ASCVD risk.

Key findings from the ARCHES-2 study include:
- Zodasiran treatment led to dose-dependent reductions in triglycerides, remnant cholesterol, LDL-C, ApoB, and Non-HDL-C.
- At week 24, dose levels of 50, 100, and 200 mg resulted in placebo-adjusted triglyceride reductions of 51%, 57%, and 63%, respectively.
- Reductions in ANGPTL3 were noted to be 54%, 70%, and 74% compared to placebo, with corresponding drops in remnant cholesterol of 73%, 76%, and 82%.
- Additional significant reductions were observed at the 200 mg dose level: LDL-C by 20%, ApoB by 22%, and Non-HDL-C by 36%.
- A subset of patients with higher baseline liver fat saw dose-dependent reductions in liver fat, with the 200 mg dose achieving a 28% reduction compared to 2% for the placebo group.

The safety profile of zodasiran in the ARCHES-2 study was favorable, with comparable rates of treatment-emergent adverse events between the treatment and placebo groups. There were no significant changes in laboratory safety assessments, platelet counts, or mean HbA1c levels.

The ARCHES-2 trial was a double-blind, placebo-controlled study involving 204 participants with mixed hyperlipidemia. Participants had fasting triglyceride levels between 150-499 mg/dL and either LDL-C above 70 mg/dL or Non-HDL-C above 100 mg/dL. The study's primary goal was to assess the safety and efficacy of zodasiran in this population.

Mixed hyperlipidemia, also known as mixed dyslipidemia, is characterized by elevated levels of LDL-C and triglycerides. Despite existing therapies that lower LDL-C levels and reduce ASCVD risk, considerable residual risk remains due to elevated non-HDL cholesterol driven by remnant cholesterol in triglyceride-rich lipoproteins. Genetic and epidemiological studies support the causal role of these lipoproteins in ASCVD.

Zodasiran, formerly referred to as ARO-ANG33, is a pioneering RNA interference (RNAi) therapy designed to inhibit the production of angiopoietin-like protein 3 (ANGPTL3), a liver-expressed regulator of lipid metabolism. By targeting ANGPTL3, zodasiran enhances the activity of lipoprotein lipase and endothelial lipase, leading to decreased levels of atherogenic lipoproteins and, potentially, a reduced ASCVD risk.

Arrowhead Pharmaceuticals specializes in developing RNAi-based therapies that silence disease-causing genes, offering a promising avenue for treating various intractable diseases.