Arrowhead Pharmaceuticals says its experimental RNAi therapy ARO-DIMER-PA has delivered substantial reductions in two key genes linked to cardiovascular risk, marking an early clinical test of a single molecule designed to silence both targets simultaneously.

 

Interim Phase 1/2a data showed that single doses of ARO-DIMER-PA produced mean maximum reductions of 72% in PCSK9 and 88% in APOC3 in patients with mixed hyperlipidemia, the company said.

 

The treatment also produced significant changes across several blood-lipid measures. Mean maximum reductions included 54% in LDL-C, 73% in triglycerides, 61% in non-HDL cholesterol and 50% in apolipoprotein B (ApoB).

 

Arrowhead described the findings as the first clinical validation of its proprietary approach to silencing two genes with one RNAi molecule.

 

“With these interim topline results, Arrowhead’s innovative and proprietary Targeted RNAi Molecule (TRiM) platform has achieved clinical validation of its ability to target and silence two genes simultaneously in one molecule. This represents an important step forward and a first for the field of RNAi therapeutics. We look forward to presenting additional details on this groundbreaking advance at an upcoming medical congress,” said Chris Anzalone, President and CEO at Arrowhead Pharmaceuticals. 

 

“This validation potentially expands the number of diseases and patients worldwide that may be helped by Arrowhead’s RNAi therapies. ARO-DIMER-PA also fits well strategically with Arrowhead’s growing focus on cardiometabolic diseases. 

 

'It is complemented by our existing portfolio, which includes our first commercial product REDEMPLO (plozasiran), now approved in the U.S., European Union, Canada, Australia, and China for the treatment of familial chylomicronemia syndrome (FCS), and investigational zodasiran, which is currently being studied in the global Phase 3 YOSEMITE clinical trial in patients with homozygous familial hypercholesterolemia (HoFH).”

 

 

ARO-DIMER-PA is designed to silence PCSK9 and APOC3 in liver cells. Both genes are associated with lipid metabolism, and targeting them together is intended to address multiple lipid abnormalities with a single therapy.

 

The company said the early data provide evidence that simultaneous silencing of the two genes can translate into broad changes in atherogenic lipids and lipoproteins.

 

James Hamilton, Chief Medical Officer and head of R&D at Arrowhead, added, "The relationship between low-density lipoprotein-cholesterol (LDL-C) and Apolipoprotein B (ApoB) reduction and cardiovascular risk is one of the most consistently replicated findings in modern medicine. 

 

"Over the past three decades, numerous clinical studies have shown that lowering these markers translates into fewer heart attacks, strokes, and cardiovascular deaths. 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.”

 

Steven Nissen, 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, added, “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. This medication represents a new approach to targeting multiple lipid abnormalities with a single therapy.”

 

 

The single-dose escalation portion of the trial has been completed through 400 mg. Arrowhead said the most commonly reported treatment-emergent adverse events were injection-site events and headaches.

 

No drug-related serious adverse events were reported, according to the company.

 

The study is continuing to evaluate the safety and tolerability of multiple doses, meaning the current findings remain interim and early-stage.

 

 

Mixed hyperlipidemia is characterized by elevated LDL cholesterol and triglycerides and is associated with a heightened risk of atherosclerotic cardiovascular disease.

 

Arrowhead says ARO-DIMER-PA is the first clinical candidate specifically designed to silence two genes using a single RNAi molecule.

 

The ongoing ARO-DIMER-PA-1001 study is a placebo-controlled Phase 1/2a dose-escalation trial evaluating safety, tolerability, pharmacokinetics, pharmacodynamics and lipid effects. The study is designed to enroll up to 78 adults with mixed hyperlipidemia.