ARO-DIMER-PA Silences PCSK9, APOC3 in Mixed Hyperlipidemia

Arrowhead Pharmaceuticals has announced interim topline data from a Phase 1/2a trial of ARO-DIMER-PA, an investigational dual-functional RNA interference (RNAi) molecule designed to silence both PCSK9 and APOC3 in patients with mixed hyperlipidemia.¹

Residual atherosclerotic cardiovascular disease (ASCVD) risk persists in patients with mixed hyperlipidemia even with intensive statin therapy and PCSK9 inhibition. ARO-DIMER-PA extends Arrowhead's cardiometabolic pipeline, which already includes plozasiran (REDEMPLO), approved for familial chylomicronemia syndrome, and zodasiran, currently in the Phase 3 YOSEMITE trial for homozygous familial hypercholesterolemia. Combining PCSK9 and APOC3 silencing in 1 molecule targets both LDL-C and triglyceride-rich remnant lipoproteins simultaneously.¹

“Mixed hyperlipidemia is not adequately addressed by treating LDL-C alone. Even with intensive statin therapy and PCSK9 inhibitors, substantial ASCVD risk remains, and triglyceride-rich remnant lipoproteins may be an important part of that residual risk,” Steven Nissen, MD, chief academic officer for the Heart and Vascular Institute at the Cleveland Clinic, the Lewis and Patricia Dickey Chair in Cardiovascular Medicine and Professor of Medicine at the Lerner College of Medicine, said in a statement. “This medication represents a new approach to targeting multiple lipid abnormalities with a single therapy.”¹

ARO-DIMER-PA Topline Results

ARO-DIMER-PA-1001 is a placebo-controlled, dose-escalating Phase 1/2a study enrolling ≤78 adults with mixed hyperlipidemia. Part 1 evaluates single ascending doses of ARO-DIMER-PA, and part 2 will assess multiple-dose regimens, with pharmacokinetics, pharmacodynamics, and effects on LDL-C and triglycerides (TG) as key study parameters. According to Arrowhead Pharmaceuticals, single-dose escalation has been completed through 400 mg.²

In the interim single-dose analysis, ARO-DIMER-PA produced dose-dependent mean maximal reductions in serum PCSK9 of 72% and APOC3 of 88%. Concurrent silencing of both targets translated into a mean maximal LDL-C reduction of 54%, a TG reduction of 73%, a non-high-density lipoprotein (non-HDL) cholesterol reduction of 61%, and an apolipoprotein B (ApoB) reduction of 50%.¹

ARO-DIMER-PA safety and tolerability in single-dose escalation

Beyond the primary lipid and lipoprotein reductions, Arrowhead highlighted the dual-target mechanism itself as a key secondary finding. Silencing PCSK9 and APOC3 with a single molecule produced concurrent reductions across LDL-C, TG, non-HDL cholesterol, and ApoB, a pattern the company says supports a broader effect on atherogenic lipoprotein burden than PCSK9 or APOC3 silencing alone would be expected to achieve.¹

On safety, Arrowhead reported the most commonly observed treatment-emergent adverse events (TEAEs) were injection-site reactions and headache. No drug-related serious adverse events occurred during single-dose escalation through 400 mg, according to the company. The study is continuing to evaluate the safety and tolerability of multiple-dose regimens in part 2.¹

“Over the past 3 decades, numerous clinical studies have shown that lowering [LDL-C and ApoB] translates into fewer heart attacks, strokes, and cardiovascular deaths,” James Hamilton, MD, MBA, chief medical officer and head of R&D at Arrowhead, said in a statement. “The early single dose data with ARO-DIMER-PA in patients with mixed hyperlipidemia give us a high degree of confidence that the robust reductions in LDL-C and ApoB that we have seen, along with robust reductions in additional atherogenic lipoproteins, have the potential to translate into a reliable clinical benefit in later stage studies.”¹

References

1. Arrowhead Pharmaceuticals. Arrowhead Pharmaceuticals Announces Interim Topline Clinical Data for the First Dual-Functional RNAi Therapeutic for the Treatment of Mixed Hyperlipidemia. BusinessWire. Published September 15, 2026. Accessed September 15, 2026. https://www.businesswire.com/news/home/20260915705822/en/Arrowhead-Pharmaceuticals-Announces-Interim-Topline-Clinical-Data-for-the-First-Dual-Functional-RNAi-Therapeutic-for-the-Treatment-of-Mixed-Hyperlipidemia

2. Arrowhead Pharmaceuticals. Study of ARO-DIMERPA in Adult Participants With Mixed Hyperlipidemia. ClinicalTrials.gov Identifier: NCT07223658. Updated August 18, 2026. Accessed September 15, 2026. https://clinicaltrials.gov/study/NCT07223658