Slide 1: Systemic RNAi Targeting MAPT: Advancing Tau Suppression Across the CNS with TRiM SC
Systemic RNAi Targeting MAPT: Advancing Tau Suppression Across the CNS with TRiM SC Kayal Madhivanan, Ph.D., Arrowhead Pharmaceuticals TIDES USA 2026
Slide 2: Safe Harbor Statement
Safe Harbor Statement This presentation contains forward-looking statements within the meaning of the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995. These statements are based upon our current expectations and speak only as of the date hereof. Our actual results ma
Slide 3: Toxic MAPT/Tau protein aggregation: Key driver in Tauopathies including Alzheimer's Disease
Toxic MAPT/Tau protein aggregation: Key driver in Tauopathies including Alzheimer’s Disease Microtubule-associated protein tau (MAPT) gene encodes tau protein: • Abundant in neurons of CNS, less in astrocytes and oligodendrocytes • Promotes stabilization of microtubules in axons • Intrinsically diso
Slide 4: Tauopathies: A spectrum from Common to Rare
Tauopathies: A spectrum from Common to Rare • 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 morpholog
Slide 5: Tau Pathology Correlates with Cognitive Decline in Alzheimer's Disease
Tau Pathology Correlates with Cognitive Decline in Alzheimer’s Disease • Amyloid cascade hypothesis is: amyloid plaque → Tau tangles → cognitive decline Amyloid plaque precedes Tau pathology • Tau neurofibrillary tangle pathology but not amyloid predicts cognitive decline • Anti-amyloid therapies ha
Slide 6: TRiM Platform: Targeted RNAi Molecule
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
Slide 7: TRiM Platforms Drive Robust Pipeline for Multiple Tissue Types
TRiM Platforms Drive Robust Pipeline for Multiple Tissue Types Liver Lung Skeletal CNS Adipose Ocular Cardio- Muscle myocyte Strong Deep lung clinical clinical Early clinical Early clinical Early clinical Preclinical Preclinical validation validation stage stage stage stage stage (RAGE) ❖ Arrowhead
Slide 8: TRiM BBB Platform for siRNA Delivery to CNS
TRiM BBB Platform for siRNA Delivery to CNS Systemic Delivery Platform ❖ 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 8
Slide 9: TRiM BBB Platform Binds to Apical Domain of TfR1
TRiM BBB Platform Binds to Apical Domain of TfR1 TRiM BBB ligand TfR1 ➢ Cryo-EM structure Fe3+ comprising TRiM BBB Fe3+ ligand, human TfR, and Diferric Tf endogenous Tf, shows apical domain binding Fe3+ Fe3+ ➢ TRiM BBB ligand does not interfere with endogenous Tf binding Endogenous Tf 9
Slide 10: BBB Platform Demonstrated to Cross BBB in hTfR Tg Mouse
BBB Platform Demonstrated to Cross BBB in hTfR Tg Mouse siRNA Delivery in Hippocampus siRNA Concentration in Half Brain WT Mouse Tg Mouse 1.5 mpk, SC Sac 24 h post-dose 56x 100 Relative Concentration 80 60 40 20 10 8 siRNA signal in red 6 1.5 mpk, SC, 4 24 h post-dose 2 0 WT Mouse Tg Mouse ➢ TRiM BB
Slide 11: PS19 × hTFR1: A Tauopathy Model with Human TfR1-Mediated CNS Delivery
PS19 × hTFR1: A Tauopathy Model with Human TfR1-Mediated CNS Delivery ➢ 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-
Slide 12: BBB Platform Displays Dose-Dependent Delivery and mRNA Target Engagement in Mouse CNS
BBB Platform Displays Dose-Dependent Delivery and mRNA Target Engagement in Mouse CNS Dose Response Effect on MAPT mRNA Reduction by CNS Region PS19 × hTFR1 tauopathy model: D15 post last-dose Cortex Hippocampus Thoracic Spinal Cord Relative Trigger Conc. (pmol/g) 1.2 50 1.2 40 1.2 25 1.0 1.0 1.0 Re
Slide 13: MAPT mRNA Knockdown Translates to Reduced AT8-Positive Tau Pathology
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 Control Treated 1.5 Relative MAPT mRNA Expression 1.0 0.5 0.0 d s x pu te or or lC am C a oc in Sp p ip c H ci ora Th 13
Slide 14: BBB Platform Achieves Improved Delivery to Deep Brain Regions
BBB Platform Achieves Improved Delivery to Deep Brain Regions siRNA Concentrations in siRNA Concentrations in NHP Brain regions by IT NHP Brain regions by SC IT, 15 mg, D1 SC, 3 x 3 mpk, qw: Sac D29 D1, D8, D15 Sac D29 25 5 Relative Concentration 21.6 Relative Concentration 20 4 3.6 < 2x 3.3 15 22x
Slide 15: BBB Platform Achieves Uniform Reduction Across the Brain
BBB Platform Achieves Uniform Reduction Across the Brain MAPT mRNA reduction in MAPT mRNA reduction in NHP Brain regions by IT NHP Brain regions by SC Intrathecal administration: Subcutaneous administration: ➢ Minimal mRNA reduction in deep brain regions ➢ Even mRNA reduction across brain regions, i
Slide 16: ARO-MAPT Achieves Deep Knockdown of MAPT mRNA Throughout the CNS with SC Administration
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 3 x 3 mpk, SC, qw, D29 1x 1x 2.0 Control ARO-MAPT Control ARO-MAPT SC 1.5 Relative Expression 1.0 20x 20x 0.5 0.25 0.0 ns Pu te
Slide 17: ARO-MAPT Achieves Deep Knockdown of MAPT mRNA Throughout the CNS with SC Administration
ARO-MAPT Achieves Deep Knockdown of MAPT mRNA Throughout the CNS with Subcutaneous Administration MAPT mRNA Reduction in NHP CNS Regions 3 x 3 mpk, SC, qw, D29 2.0 Control ARO-MAPT 1.5 Relative Expression ➢ At 3 x 3 mpk, 70-80% MAPT mRNA 1.0 reduction was achieved across all brain regions, including
Slide 18: ARO-MAPT Achieves MAPT mRNA Reduction Across All Major CNS Cell Types
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 Control ARO-MAPT dosed 3 x 3 mpk, SC, D29 ❖ MAPT: brown puncta ❖ Neurons: green ❖ Astrocytes: yellow ❖ Microglia: purple ❖ Oligodendrocytes: teal 18
Slide 19: ARO-MAPT maintains months of durable knockdown throughout the brain in NHP
ARO-MAPT maintains 3 months of durable knockdown throughout the brain in NHP Duration of MAPT mRNA/ Tau protein Reduction in NHP 3x3mpk qw, SC 1 .0 Frontal Cortex mRNA Hippocampus mRNA MAPT mRNA/Tau protein 0 .8 Frontal Cortex protein Relative to control Hippocampus protein ➢ Durable target engageme
Slide 20: PK/PD Modeling Projects Sustained Tau Inhibition with Quarterly Dosing of ARO-MAPT
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 150 1800 100 Tau mRNA (% of Control) Mean CNS Conc. (ng/g) mRNA KD Predicted 125 1500 80 Control Group (% of Control) 1x3 mpk, qw,
Slide 21: Sustained inhibition of Tau Protein After Repeat Dosing
Sustained inhibition of Tau Protein After Repeat Dosing 7x3 mg MAPT siRNA/kg SC: 3 weekly loading doses + 4 monthly maintenance doses Study Day: 1 8 15 43 71 99 127 156 239 Necropsy Necropsy Duration of MAPT mRNA Reduction in NHP Duration of Tau protein Reduction in NHP PBS Control D156: 4 weeks pos
Slide 22: Tau Protein reduction in Cerebrospinal Fluid Follows Reduction in CNS Tissues
Tau Protein reduction in Cerebrospinal Fluid Follows Reduction in CNS Tissues T-Tau Levels in CSF Last dose 1.0 to individual pre-dose 0.8 t-tau normalized ➢ Tau protein reduction maintained 0.6 at 50-60% up to 4 months after last-dose. 0.4 0.2 0.0 0 50 100 150 200 250 n=2 to 5 at each timepoint; Me
Slide 23: ARO-MAPT Profile
ARO-MAPT Profile Productive Efficacy & Activity Duration & Formulation Toxicology Profile Delivery Across Profile in NHP Dosing Schedule BBB ➢ siRNA delivery ➢ Deep and ➢ Duration of ➢ Formulation ➢ No changes demonstrated durable target target reduction supports SC by tissue- reduction across ≥ 3 m
Slide 24: Study Design of Phase 1/2a Placebo-controlled Dose-escalating Study
Study Design of Phase 1/2a Placebo-controlled Dose- escalating Study Purpose: To evaluate the safety, tolerability, PK, and PD of ARO-MAPT-SC compared to placebo in adult healthy volunteers and in participants with early Alzheimer’s disease, defined as mild cognitive impairment due to AD and mild AD
Slide 25: ARO-MAPT-SC-1001 Phase 1/2a Clinical Study
ARO-MAPT-SC-1001 Phase 1/2a Clinical Study Primary Endpoint Key Exploratory Endpoints Sites Safety and • CSF t-tau, p-tau217, p-tau 181, New Zealand tolerability of MTBR tau (Dosed Adult Healthy ARO-MAPT-SC in Volunteers – 12/2025) patients with Early AD† • Plasma p-tau 217 United Kingdom • Function
Slide 26: Thank you!
San Diego, CA Pasadena, CA Thank you! Verona, WI Madison, WI Questions? Answers. 26