Arrowhead Pharmaceuticals Reports Up to 73% CSF Tau Reduction in Early ARO-MAPT Study

Key Points

• ARO-MAPT reduced CSF total tau by up to 73% on average in early healthy-volunteer data, with an individual reduction of up to 85% and evidence of a dose response. The treatment was reportedly well tolerated, with no serious treatment-emergent adverse events, neurobehavioral events or persistent anemia observed so far.
• The results provide Arrowhead’s first clinical proof of concept for delivering siRNA to the central nervous system through a subcutaneous injection. The company believes the TRiM CNS platform could eventually enable infrequent, potentially at-home dosing, though further studies are needed.
• Arrowhead is continuing ARO-MAPT trials in early Alzheimer’s disease and is discussing potential later-stage studies in progressive supranuclear palsy and MAPT-related frontotemporal dementia, with possible trial starts targeted for 2027.

Arrowhead Pharmaceuticals NASDAQ: ARWR presented interim Phase I/II data for ARO-MAPT, an investigational small interfering RNA therapy designed to reduce tau protein expression in the central nervous system, alongside initial clinical results for its TRiM CNS delivery platform.

The company said the platform uses a transferrin receptor 1-targeted Fab linked to an siRNA payload, with the goal of enabling subcutaneous administration and delivery across the blood-brain barrier. ARO-MAPT targets the MAPT gene, which produces tau, a protein implicated in Alzheimer’s disease and primary tauopathies including progressive supranuclear palsy, corticobasal degeneration and some forms of frontotemporal dementia.

Early healthy-volunteer data show tau reductions

James Hamilton, Arrowhead’s Head of R&D and Chief Medical Officer, said interim data from single-ascending-dose healthy-volunteer cohorts showed mean reductions in cerebrospinal fluid, or CSF, total tau of up to 73% following an initial loading dose. The largest individual reduction was up to 85%, he said.

Hamilton said the data showed evidence of a dose response, while placebo recipients showed no reductions in CSF tau. The company characterized the response as generally consistent across treated individuals.

Available safety findings supported continued dosing and further development, according to Hamilton. He said ARO-MAPT had been well tolerated to date, with no reported serious treatment-emergent adverse events, no neurobehavioral events such as confusion, and no persistent anemia.

The ongoing ARO-MAPT-SC-1001 study is designed to assess safety, pharmacokinetics and pharmacodynamic effects in healthy volunteers and people with early Alzheimer’s disease. Healthy-volunteer enrollment has been completed, while enrollment in Alzheimer’s patient cohorts is ongoing at sites in Canada, the U.K., Australia and New Zealand.

Arrowhead plans to provide additional data from multiple-ascending-dose healthy-volunteer cohorts in 2027 and expects an update from its Alzheimer’s patient cohorts that year as well.

Company highlights subcutaneous CNS delivery

Chief Executive Officer Chris Anzalone said the results represent Arrowhead’s first clinical proof of concept for delivery of siRNA to the central nervous system through a subcutaneous injection. He said the company believes the approach could potentially support dosing as infrequently as quarterly and, if developed successfully, could potentially be administered at home.

In preclinical monkey studies, Arrowhead said subcutaneous administration of ARO-MAPT reduced MAPT expression by more than 75% across multiple brain regions, including the hippocampus. The company also reported that repeat dosing in monkeys maintained gene silencing and supported up to 60% CSF tau knockdown four months after the last dose.

Hamilton said Arrowhead’s preclinical work suggested more homogeneous brain distribution from the subcutaneous platform than from intrathecal administration, which delivers drugs directly into spinal fluid. He said broader distribution could avoid high concentrations in the spinal cord and potentially improve silencing in disease-relevant brain regions.

Anzalone said the company has one wholly owned and one partnered CNS candidate in clinical development using the TRiM CNS platform, and expects another partnered candidate to enter the clinic in 2027. Arrowhead also plans to introduce at least three additional wholly owned CNS candidates into the clinic over the next 12 months, according to his remarks.

Tau remains an emerging therapeutic target

Adam Boxer, a professor of neurology at the University of California, San Francisco, reviewed the rationale for reducing tau in neurodegenerative diseases. He said the amount and location of insoluble tau in the brain are closely correlated with symptoms in Alzheimer’s disease and several primary tauopathies.

Boxer noted that two approved anti-amyloid therapies have shown modest slowing of cognitive decline in symptomatic Alzheimer’s disease, but said tau-directed treatments may provide another way to address disease progression. He discussed prior studies of tau-targeting antisense therapies, including results suggesting reductions in CSF tau and signals of slowed cognitive decline or neurodegeneration in certain settings.

However, Boxer said important questions remain regarding the optimal degree and duration of tau reduction. Tau has normal physiological roles, and while animal studies and human genetic evidence have not linked tau loss of function to disease, prior clinical findings with another tau-lowering therapy raised questions about whether adverse effects could result from the treatment approach or potentially from on-target tau reduction.

Potential next studies in PSP and FTD

Arrowhead said it has begun regulatory discussions regarding potential later-stage studies in MAPT-variant frontotemporal dementia and progressive supranuclear palsy. Hamilton said the company aims to finalize study designs following additional regulatory discussions over the next one to two quarters, with a goal of starting studies in 2027.

Boxer said PSP and certain forms of frontotemporal dementia may offer potential development advantages because they are rare, severe diseases with no approved disease-modifying therapies and generally faster clinical progression than Alzheimer’s disease. He added that clinical studies in these conditions can potentially be smaller and shorter, although he did not provide a specific regulatory outlook for ARO-MAPT.

In discussing future dose selection, Hamilton said the 6.4 mg/kg and 12.8 mg/kg regimens appeared broadly comparable after the initial loading dose. He said Arrowhead may favor the lower end of the range if higher doses do not show added benefit, though patient data and results after subsequent doses will be needed to guide that decision.

About Arrowhead Pharmaceuticals (NASDAQ:ARWR)

Arrowhead Pharmaceuticals, Inc is a biopharmaceutical company focused on developing medicines that silence disease-causing genes. Its research is based primarily on RNA interference (RNAi), a biological process that reduces the production of specific proteins by targeting messenger RNA before it can be used to make those proteins.

The company uses its proprietary Targeted RNAi Molecule (TRiM) platform to design and deliver RNAi therapeutics to selected tissues, including the liver and lungs.

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