Arrowhead Pharmaceuticals Advances Two Breakthrough RNAi Therapeutics into Clinical Trials
Key Insights
Arrowhead Pharmaceuticals has filed regulatory applications for two innovative RNAi therapeutics: ARO-DIMER-PA (search) for mixed hyperlipidemia (search) and ARO-MAPT (search) for Alzheimer's disease (search).
ARO-DIMER-PA (search) represents the first dual-functional RNAi therapeutic designed to simultaneously target PCSK9 and APOC3 genes to reduce cardiovascular disease risk.
ARO-MAPT (search) utilizes a novel CNS delivery system that achieves blood-brain barrier penetration through subcutaneous administration, targeting tau protein (search) in tauopathies (search).
Arrowhead Pharmaceuticals has filed regulatory applications to initiate clinical trials for two groundbreaking RNA interference (RNAi) therapeutics, marking significant advances in both cardiovascular and neurodegenerative disease treatment. The company submitted Clinical Trial Applications (CTAs) to the New Zealand Medicines and Medical Devices Safety Authority for ARO-DIMER-PA (search), targeting mixed hyperlipidemia (search), and ARO-MAPT (search), designed for Alzheimer's disease (search) treatment.
First Dual-Target RNAi Therapeutic for Cardiovascular Disease
ARO-DIMER-PA (search) represents a pioneering achievement in the RNAi field as the first clinical candidate designed to target two genes simultaneously within a single molecule. The therapeutic is engineered to silence expression of both the proprotein convertase subtilisin kexin 9 (PCSK9) and apolipoprotein C3 (APOC3) genes, leveraging Arrowhead's proprietary Targeted RNAi Molecule (TRiM™) platform.
"Arrowhead is at the forefront of innovation in the RNAi field and the expansion of the TRiM™ platform to now include a clinical stage candidate that can potentially silence expression of two genes in one RNAi molecule further reinforces our leadership position," said Chris Anzalone, Ph.D., President and CEO at Arrowhead.
Mixed hyperlipidemia (search), characterized by elevated low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG) levels, represents a major risk factor for atherosclerotic cardiovascular disease (search) (ASCVD), which is the leading cause of mortality worldwide. Despite existing LDL-C-lowering therapies, substantial residual risk persists in patients with mixed hyperlipidemia.
The planned Phase 1/2a study will be a randomized, double-blind, placebo-controlled, dose-escalating trial evaluating safety, tolerability, pharmacokinetics, pharmacodynamics, and effects on LDL-C and triglycerides. The study will enroll up to 78 adult subjects with mixed hyperlipidemia (search) across two parts: Part 1 examining single-dose administration and Part 2 evaluating multiple doses.
Novel CNS Delivery System for Alzheimer's Disease
ARO-MAPT (search) represents Arrowhead's first investigational RNAi therapy utilizing a new proprietary delivery system capable of achieving blood-brain barrier penetration and deep knockdown of target genes across the central nervous system (CNS) after subcutaneous injections. The therapeutic targets the microtubule associated protein tau (MAPT (search)) gene, which encodes the tau protein (search) whose aggregation is believed to drive multiple tauopathies (search), including Alzheimer's disease (search).
"ARO-MAPT (search) is a potential treatment for Alzheimer's disease (search) designed to achieve delivery to deep brain regions after subcutaneous administration," said James Hamilton, M.D., Chief Medical Officer and Head of R&D at Arrowhead. "The tau protein (search), which is the target of ARO-MAPT, has strong correlation with symptom severity and is a promising therapeutic target for Alzheimer's disease and other tauopathies (search)."
Alzheimer's disease (search) affects an estimated 32 million people worldwide and represents the most common cause of dementia (search). The disease is part of a group of neurodegenerative conditions called tauopathies (search), marked by abnormal accumulation and formation of tau tangles in neurons.
Preclinical Data Demonstrates CNS Efficacy
Preclinical studies presented at the RNA Leaders USA Congress 2025 demonstrated that ARO-MAPT (search) achieved potent and long-lasting MAPT (search) mRNA and tau protein (search) suppression with uniform distribution throughout the CNS after subcutaneous administration in non-human primates. The data showed improved delivery and knockdown of mRNA and protein throughout the CNS compared to intrathecal administration, with long-lasting protein reduction potentially enabling monthly or quarterly subcutaneous dosing.
The Phase 1/2a study for ARO-MAPT (search) will be a placebo-controlled dose-escalating trial evaluating safety, tolerability, pharmacokinetics, and pharmacodynamics in up to 64 healthy subjects and up to 48 subjects with early Alzheimer's disease (search), defined as mild cognitive impairment due to Alzheimer's disease and mild Alzheimer's disease dementia (search). The study design includes multiple dosing regimens: Part 1a with one or three weekly doses, and Parts 1b and 2a with three weekly doses followed by three monthly doses for a total of six subcutaneous administrations.
Strategic Portfolio Expansion
The advancement of both therapeutics aligns with Arrowhead's growing commercial focus on RNAi therapeutics in the cardiometabolic therapeutic area. The company has an upcoming November 18, 2025, PDUFA date for plozasiran, representing its first potential commercial product, and an ongoing Phase 3 trial for zodasiran in homozygous familial hypercholesterolemia (search) (HoFH).
"The addition of ARO-DIMER-PA (search) fits well strategically with our growing commercial focus on RNAi therapeutics in the cardiometabolic therapeutic area," Anzalone noted. The filing of ARO-MAPT (search)'s CTA represents further expansion of the TRiM™ platform, which currently includes active clinical programs delivering siRNA to liver, lung, skeletal muscle, CNS, and adipose tissue.