Arrowhead Pharmaceuticals : TIDES 2026 KM final (1)

Published: 2026-05-13 16:53:17 ET ARWR

Published on 05/13/2026 at 04:53 pm EDT

Systemic RNAi Targeting MAPT: Advancing Tau Suppression Across the CNS with TRiM SC

Kayal Madhivanan, Ph.D., Arrowhead Pharmaceuticals TIDES USA 2026

Abundant in neurons of CNS, less in astrocytes and oligodendrocytes

Promotes stabilization of microtubules in axons

Intrinsically disordered and subject to many

post-translational modifications

Hyperphosphorylation promotes intracellular formation of neurofibrillary tangles which are correlated with neurodegeneration

Querfurth & LaFerla, N Engl J Med, 2010

Toxic MAPT/Tau protein aggregation:

Key driver in Tauopathies including Alzheimer's Disease

Heterogeneous group of ~20 neurodegenerative diseases characterized by abnormal intracellular deposition of tau in neurons and glial cells

Further classified by the relative balance of 3R & 4R tau isoforms found in pathological inclusions and morphological/ ultrastructural features of inclusions.

Major tauopathies:

Alzheimer's disease (>7M in U.S.)

Frontotemporal lobar degeneration dementia (FTLD) associated with Tau (~25-30K)

Progressive supranuclear palsy (PSP) (~20K)

Familial FTLD-MAPT due to MAPT mutation (1-5K)

Adapted from Tagai et al., Neuron, 2021.

A single siRNA targeting MAPT has the potential to address all these diseases.

Tauopathies: A spectrum from Common to Rare

Amyloid cascade hypothesis is:

Amyloid plaque precedes Tau pathology

amyloid plaque → Tau tangles → cognitive decline

Tau neurofibrillary tangle pathology but not amyloid predicts cognitive decline

Anti-amyloid therapies have shown no Tau reduction, are less effective in patients with high Tau burden, and have significant safety risks

Tau reduction has potential for benefit in broader patient population with better safety profile

Jack et al., Lancet Neurol, 2010.

Tau Pathology Correlates with Cognitive Decline in Alzheimer's Disease

TRiM Platform: Targeted RNAi Molecule

A modular system comprising:

Unique RNAi chemistry insights and expertise

Powerful platform technology to maximize

activity and stability employing:

Algorithmic approach to sequence selection and design

Stabilization chemistry

Targeting ligand

Linker chemistry

PK and PD enhancers

Liver

Strong clinical validation

Lung

Deep lung clinical validation (RAGE)

Skeletal Muscle

Early clinical

stage

CNS

Early clinical stage

Adipose

Early clinical stage

Ocular

Preclinical

stage

Cardio-myocyte

Preclinical stage

Arrowhead is leading the field in extrahepatic delivery of the siRNA drug modality

We have built experience and tools to achieve productive RNAi in new tissues and cell types

TRiM

Platforms Drive Robust Pipeline for Multiple Tissue Types

Subcutaneous (SC) administration for crossing blood-brain barrier (BBB)

siRNA conjugated to a TfR-targeting ligand through a stable, non-reversible covalent linkage

Stable in circulation

TRiM

BBB Platform for siRNA Delivery to CNS

Systemic Delivery Platform

TRiM BBB ligand

TfR1

Fe3+

Diferric Tf

Fe3+

Cryo-EM structure comprising TRiM BBB ligand, human TfR, and endogenous Tf, shows apical domain binding

TRiM BBB ligand does not interfere with endogenous Tf binding

Endogenous Tf

TRiM

BBB Platform Binds to Apical Domain of TfR1

WT Mouse

Tg Mouse

siRNA signal in red

1.5 mpk, SC,

24 h post-dose

1.5 mpk, SC Sac 24 h post-dose

TRiM BBB platform is human/cyno cross-reactive

Delivery assessed in transgenic (Tg) mice expressing human Transferrin receptor

siRNA quantitation shows over 50x difference between Tg and control group

BBB Platform Demonstrated to Cross BBB in hTfR Tg Mouse

siRNA Delivery in Hippocampus

siRNA Concentration in Half Brain

PS19 mice express human P301S mutant tau:

Develop progressive neurofibrillary tangle pathology from ~6 months.

Yoshiyama et al., Neuron 2007 · Takeuchi et al., PLOS ONE 2011

Crossed with hTFR1 transgenic mice to enable TfR1-dependent siRNA delivery.

Model allows assessment of both MAPT knockdown and reduction of pathological phospho-tau species in the same animal.

PS19 × hTFR1: A Tauopathy Model with Human TfR1-Mediated CNS Delivery

Dose Response Effect on MAPT mRNA Reduction by CNS Region

PS19 × hTFR1 tauopathy model: D15 post last-dose

Relative Expression

1.2

Cortex

50 1.2

Hippocampus

1.2

Thoracic Spinal Cord

Relative Trigger Conc. (pmol/g)

1.0

0.8

0.6

0.4

0.2

1.0

0.8

0.6

0.4

10 0.2

1.0 20

0.8

20 0.6

0.4

0.2

0.0

0 2 4 6 8 10

Cumulative Dose (mpk)

0.0

0 2 4 6 8 10

Cumulative Dose (mpk)

0.0

0 2 4 6 8 10

Cumulative Dose (mpk)

Increasing siRNA tissue concentration drives proportional MAPT mRNA reduction across all CNS regions

BBB Platform Displays Dose-Dependent Delivery and mRNA Target Engagement in Mouse CNS

Control

Treated

1.5

Relative MAPT mRNA Expression

1.0

0.5

Cortex

Hippocampus

Thoracic Spinal Cord

0.0

MAPT mRNA Knockdown Translates to Reduced AT8-Positive Tau Pathology

PS19 x hTfR1 mice:

3mg/kg:

MAPT mRNA reduction

Phospho-Tau reduction in the Hippocampus

21.6

11.0

1.0

3.6

3.3

2.0

1.0

Intrathecal administration:

Relatively limited delivery to deep brain regions

Subcutaneous administration:

Good distribution of siRNA across different brain regions.

BBB Platform Achieves Improved Delivery to Deep Brain Regions

siRNA Concentrations in

NHP Brain regions by IT

siRNA Concentrations in

NHP Brain regions by SC

Intrathecal administration:

Minimal mRNA reduction in deep brain regions

Subcutaneous administration:

Even mRNA reduction across brain regions, including deep brain.

BBB Platform Achieves Uniform Reduction Across the Brain

MAPT mRNA reduction in

NHP Brain regions by IT

MAPT mRNA reduction in

NHP Brain regions by SC

Control

ARO-MAPT

2.0

Relative Expression

1.5

3 x 3 mpk, SC, qw, D29

1.0

0.5

0.25

Frontal Cortex

Motor Cortex

Temporal Cortex

Caudate

Putamen

Thalamus

Hippocampus

Pons

Medulla

Cervical Spinal Cord

Lumbar Spinal Cord

0.0

ARO-MAPT SC

20x

Control

20x

mRNA knockdown corroborated by RNAscope

Thoracic Spinal Cord

MAPT mRNA shown in purple

ARO-MAPT Achieves Deep Knockdown of MAPT mRNA Throughout the CNS with Subcutaneous Administration

MAPT mRNA Reduction in NHP CNS Regions

MAPT mRNA Depletion in Hippocampus

Control

ARO-MAPT

At 3 x 3 mpk, 70-80% MAPT mRNA

reduction was achieved across all brain regions, including brain stem and deep brain

Up to 85% knockdown in some cortex regions

2.0

3 x 3 mpk, SC, qw, D29

Relative Expression

1.5

1.0

0.5

0.25

Frontal Cortex

Motor Cortex

Temporal Cortex

Caudate

Putamen

Thalamus

Hippocampus

Pons

Medulla

Cervical Spinal Cord

Thoracic Spinal Cord

Lumbar Spinal Cord

0.0

ARO-MAPT Achieves Deep Knockdown of MAPT mRNA Throughout the CNS with Subcutaneous Administration

MAPT mRNA Reduction in NHP CNS Regions

ARO-MAPT Achieves MAPT mRNA Reduction Across All Major CNS Cell Types

RNAscope Detection of MAPT mRNA with Multiplex Cell-Type IHC in NHP Brainstem

MAPT: brown puncta

Neurons: green

Astrocytes: yellow

Microglia: purple

Oligodendrocytes: teal

1 . 0

MAPT mRNA/Tau protein Relative to control

0 . 8

0 . 6

0 . 4

3x3mpk qw, SC

Durable target engagement with ≥50% knockdown over 3 months in CNS regions including deep brain

0 . 2

0 . 0

1 8 15 29 43 99

Days

n=4/group; mean + SEM

ARO-MAPT maintains 3 months of durable knockdown throughout the brain in NHP

Duration of MAPT mRNA/ Tau protein Reduction in NHP

mRNA KD Predicted Control Group

1x3 mpk, qw, Day 29 3x3 mpk, qw, Day 29 3x3 mpk, qw, Day 43 3x3 mpk, qw, Day 99

1800

Mean CNS Conc. (ng/g)

1500

1200

900

600

300

0 60 120 180 240 300 360

Time (Day)

100

Tau mRNA (% of Control)

PK/PD profile in NHP

Monthly booster after initial 3 x 3 mpk weekly dose projected to maintain 80% KD

Quarterly dosing projected to maintain 50-70% knockdown

Predicted Human CNS Concentrations mRNA PD (all groups)

Global Mean of 17 NHP CNS Tissues

PK/PD Modeling Projects Sustained Tau Inhibition with Quarterly Dosing of ARO-MAPT

NHP Tissue Conc. vs Tau mRNA Level

Projection of ARO-MAPT PK/PD with Quarterly Dosing

Disclaimer

Arrowhead Pharmaceuticals Inc. published this content on May 13, 2026, and is solely responsible for the information contained herein. Distributed via Public Technologies (PUBT), unedited and unaltered, on May 13, 2026 at 20:52 UTC.