Arrowhead Pharmaceuticals’ investigational RNA interference (RNAi) therapy being developed for Alzheimer’s disease has been shown to reduce tau in a Phase I/IIa trial.
The study (NCT07221344) has provided clinical validation of the candidate, dubbed ARO-MAPT, to deliver siRNA across the blood-brain barrier and achieve substantial target gene knockdown in the brain.
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In healthy volunteers, subcutaneous administration of ARO-MAPT achieved deep and durable reductions in cerebrospinal fluid (CSF) total tau, with a mean reduction of up to 73% at day 105 and a maximum reduction of 85%.
ARO-MAPT was administered at either 2.1mg/kg or 6.4mg/kg on days 1, 8, and 15, or at 12.8mg/kg on days 1 and 15.
In the lower dose cohorts, mean reductions in CSF total tau were 40% and 69%, respectively, at day 105.
With benefit still being seen at day 105, which was 90 days following the final dose, Arrowhead said this supports the potential for dosing once every three months or less frequently.
While this is a significant advance for the company, the reported biomarker results are from healthy volunteers rather than patients with Alzheimer’s disease. These patients are being studied in the second part of the current Phase I/IIa study and in additional planned studies.
ARO-MAPT was generally well tolerated, with most treatment-emergent adverse events (TEAEs) being Grade 1 or mild.
“These early clinical data are exciting because they demonstrate that ARO-MAPT can achieve deep and durable reductions of tau expression in the brain following a simple subcutaneous administration, representing an important step towards developing a potential treatment for Alzheimer’s disease and other primary tauopathies,” said Christopher Anzalone, CEO of Arrowhead.
“Abnormal tau accumulation is a key feature of multiple devastating diseases, and we believe reducing tau production has the potential to offer a meaningful new approach for patients. Equally important, these results provide clinical validation of our proprietary Targeted RNAi Molecule delivery platform to potentially address multiple diseases in the central nervous system (CNS). This major scientific breakthrough further solidifies Arrowhead’s position as the leading innovator in siRNA therapies,” he added.
ARO-MAPT is designed to silence expression of the microtubule-associated protein tau (MAPT) gene, reducing production of all six isoforms of the tau protein, which is believed to be linked to Alzheimer’s disease. Pathological aggregation of tau is also believed to be linked to MAPT-related frontotemporal dementia and progressive supranuclear palsy.
In March 2026, Johnson & Johnson (J&J) announced that its anti-tau therapy posdinemab failed to show benefit in a Phase IIb trial. The anti-phosphorylated-tau (p-tau) monoclonal antibody (mAb) is no longer being developed by the big pharma company.
Other developers are targeting tau, including with anti-tau mAbs, GlobalData analysis shows. Eisai’s etalanetug is targeting a different part of the tau monomer than posidinemab and is in an ongoing Phase II/III trial, having also gained fast track designation from the US Food and Drug Administration (FDA).
Other therapies in development include TauRx’s hydromethylthionine mesylate, an oral small molecule targeting tau, and Annovis Bio’s oral small molecule buntanetap, which targets tau as well as amyloid beta precursor protein and alpha-synuclein.
Biogen is also investigating an anti-tau drug, but data released in July at the Alzheimer’s Association International Conference (AAIC) 2026 spooked investors after primary endpoint data released were not statistically significant. Biogen said cognitive scale endpoints were clinically beneficial and that the clinical dementia rating sum of boxes (CDR-SB) favoured diranersen across all studied doses.
These approaches differ from approved therapies for Alzheimer’s disease that target amyloid. Eli Lilly and Biogen/Eisai continue to have a hold on the Alzheimer’s disease market after the approvals of their therapies Kisunla (donanemab) and Leqembi (lecanemab) in 2024 and 2023, respectively.
But because both therapies target amyloid, there is an ongoing unmet need for alternative treatment approaches in Alzheimer’s disease. Given the safety concerns associated with amyloid-related imaging abnormalities (ARIA), experts agree it is encouraging to see a broader range of therapeutic options for patients emerging in the pipeline. Kisunla and Leqembi have also struggled for reimbursement in several territories, prompting urgency for a wider array of therapeutic options.
GlobalData, the parent company of Clinical Trials Arena, estimates that the value of the Alzheimer’s Disease market in the eight major markets (8MM: US, France, Germany, Italy, Spain, UK, Japan and China) in 2023 was $2.4bn and is expected to grow to $14.7bn in 2033, at a compound annual growth rate (CAGR) of 20%.
